Biheterocyclic compound

ABSTRACT

The present invention provides a compound of formula (1) and a pharmaceutical composition comprising the compound useful as a nerve regeneration promoter 
     
       
         
         
             
             
         
       
     
     wherein R 1 -L- is R 1 —OC(O)—, or the like, R 1  is hydrogen atom, optionally-substituted C 1-6  alkyl group, optionally-substituted 3- to 8-membered cycloalkyl group, or the like, R 2  is hydrogen atom or the like, Ring A is formula (2) or formula (3) wherein R 3  is hydrogen atom, optionally-substituted C 1-6  alkyl group, or the like, the part of X, Y, and Z is X═Y—Z, X—Y═Z, or X—Y—Z, X is nitrogen atom, NR 4  (R 4  is hydrogen atom, optionally-substituted C 1-6  alkyl group, or the like), or the like, Y is carbon atom or the like, and Z is carbon atom, nitrogen atom or the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/392,732, filed Apr. 24, 2019, which is a continuation of U.S. patentapplication Ser. No. 16/070,014, filed Jul. 13, 2018, issued as U.S.Pat. No. 10,323,024, which is a 371 of PCT/JP2017/000819, filed Jan. 12,2017, which claims benefit of priority to Japanese Patent ApplicationNo. 2016-173510, filed Sep. 6, 2016 and Japanese Patent Application No.2016-006205, filed Jan. 15, 2016. The entire disclosures of the priorapplications are considered part of the disclosure of the accompanyingcontinuation application, and are hereby incorporated by reference intheir entirety.

TECHNICAL FIELD

The present invention relates bicyclic heterocyclyl compounds, and aninhibitor of semaphorin, a promotor of center/peripheral nerveregeneration, a medicament for preventing/treating nerve injury disease,a medicament for preventing/treating neurological disease associatedwith neurodegeneration or ischemic deficit, or a medicament forpreventing/treating corneal disease, which comprises the bicyclicheterocyclyl compound as an active ingredient.

BACKGROUND ART

Semaphorins are endogenous proteins which are identified as a factorthat can retract the nerve growth cone and suppress the axonal growth.Until now, about 20 kinds of molecular species thereof have been known.Amongst them, class type 3 subfamily gene cluster has been studied themost. The proteins that these genes encode are known to have in vitropotent activities for inhibiting neurite outgrowth and retracting growthcone. Amongst them, semaphorin 3A (Sema3A) (Non-Patent Literatures 1 and2) has been studied the most, which can induce the growth coneretraction in cultural neuron, in a low concentration of 10 pM and in ashort time.

Some substances inhibiting the Sema3A function have been already known,such as a certain group of xanthone compounds which are obtained fromthe culture of Penicillium sp. SPF-3059 strain (International PatentOrganism Depositary, National Institute of Advanced Industrial Scienceand Technology, Accession number: FERM BP-7663) (Patent Literatures 1and 2), and xanthone derivatives which are obtained bychemically-modifying the above xanthane compounds (Patent Literature 3).

And, it has been reported that the compounds can promote re-elongatingthe nerve fiber in spinal cord of a rat spinal cord injury model (PatentLiterature 4 and Non-Patent Literature 3) and can promote regeneratingthe corneal sensory neuron of a mouse corneal graft model (PatentLiterature 5 and Non-Patent Literature 4).

PRIOR ART Patent Reference

-   [Patent Literature 1] WO 2002/09756-   [Patent Literature 2] WO 2003/062243-   [Patent Literature 3] WO 2003/062440-   [Patent Literature 4] WO 2012/018069-   [Patent Literature 5] WO 2012/115182

Non-Patent Reference

-   [Non-Patent Literature 1] Cell, 75, p 217 (1993)-   [Non-Patent Literature 2] Cell, 75, p 1389 (1993)-   [Non-Patent Literature 3] Nature Medicine, volume 3, Number 12, p    1398 (2006)-   [Non-Patent Literature 4] PLOS ONE, volume 7, Issue 11, e47716    (2012)

SUMMARY OF INVENTION Technical Problem

The purpose of the present invention may be to provide an inhibitor ofsemaphorin having a novel chemical structure, and a promotor ofcenter/peripheral nerve regeneration, a medicament forpreventing/treating nerve injury disease, a medicament forpreventing/treating neurological disease associated withneurodegeneration or ischemic deficit, a medicament forpreventing/treating corneal disease such as dry eye, or the like, whichcomprises the new inhibitor of semaphorin as an active ingredient.

Solution to Problem

The present inventors have extensively studied to reach the aboveobject, and then have found that a compound of formula (1) or apharmaceutically acceptable salt thereof (hereinafter, it may bereferred to as “the present compound”) has a semaphorin inhibitoryactivity, and thereby the present compound may be a useful medicamentfor treating or preventing neuropathic disease, neurodegenerativedisease, neurological disease associated with ischemic deficit, andcorneal disease. Based upon the new findings, the present invention hasbeen completed.

The present invention can show as follows.

Term 1

A compound of formula (1):

or a pharmaceutically acceptable salt thereofwherein

R¹-L- is R¹—OC(O)— or R¹—NHC(O)—;

R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group;

R² is hydrogen atom, hydroxy group, or carboxyl group; and

Ring A is a group of formula (2) or (3):

wherein R³ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

the part of X

Y

Z is X═Y—Z, X—Y═Z, or X—Y—Z,

X is nitrogen atom, NR⁴, or oxygen atom, provided that X is not oxygenatom in the case of formula (2),

R⁴ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

Y is carbon atom or CH, and

Z is carbon atom, CH, or nitrogen atom, provided that the combination ofX, Y, and Z should be any one of chemically-possible selections.

Term 2

The compound of Term 1 or a pharmaceutically acceptable salt thereof,which is represented by formula (1′):

wherein

R¹-L- is R¹—OC(O)— or R¹—NHC(O)—;

R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thefollowing groups of formulae (4)-(6):

formula (4):

wherein m is 1, 2, 3, 4, or 5, R⁷ is C₁₋₃ alkoxy group, amino acid group(which binds to C(O) at its N terminus), and peptide consisting of 2-3amino acid residues (which binds to C(O) at its N terminus),

formula (5):

R⁸-L²-(CH₂CH₂O)_(q)CH₂CH₂

  (5)

wherein q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ is hydroxygroup, C₁₋₃ alkoxy group, amino group which may be substituted with oneor two the same or different C₁₋₃ alkyl, amino acid group (which bindsto L² at its N terminus), or peptide consisting of 2-3 amino acidresidues (which binds to L² at its N terminus), formula (6):

wherein L³ is CH₂ or C(O), and R⁹ is hydroxy group, C₁₋₃ alkoxy group,amino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl, amino acid group (which binds to L³ at its Nterminus), or peptide consisting of 2-3 amino acid residues (which bindsto L³ at its N terminus),

the substituent(s) of the (iii) optionally-substituted C₂₋₆ alkenylgroup, and the (iv) optionally-substituted C₂₋₆ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 8-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group;

R² is hydrogen atom, hydroxy group, or carboxyl group; and

Ring A is a group of formula (2′) or (3′):

wherein R³ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup, the (iii) optionally-substituted C₂₋₆ alkenyl group, the (iv)optionally-substituted C₂₋₆ alkynyl group, the (v)optionally-substituted 3- to 8-membered cycloalkyl group, the (vi)optionally-substituted 4- to 8-membered cycloalkenyl group, the (vii)optionally-substituted 4- to 8-membered saturated aliphatic heterocyclylgroup, the (viii) optionally-substituted 5- to 10-membered unsaturatedaliphatic heterocyclyl group, the (ix) optionally-substituted 6- to10-membered aryl group, and the (x) optionally-substituted 5- to10-membered heteroaryl group are independently one or more substituentsselected independently from the group consisting of hydroxy group,methoxy group, ethoxy group, carboxyl group, carbamoyl group which maybe substituted with one or two the same or different C₁₋₃ alkyl, andamino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl,

the part of X

Y

Z is X═Y—Z, X—Y═Z, or X—Y—Z,

X is nitrogen atom, NR⁴, or oxygen atom, provided that X is not oxygenatom in the case of formula (2′),

R⁴ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent (s) of the (ii) optionally-substituted C₁₋₆alkyl group, the (iii) optionally-substituted C₂₋₆ alkenyl group, the(iv) optionally-substituted C₂₋₆ alkynyl group, the (v)optionally-substituted 3- to 8-membered cycloalkyl group, the (vi)optionally-substituted 4- to 8-membered cycloalkenyl group, the (vii)optionally-substituted 4- to 8-membered saturated aliphatic heterocyclylgroup, the (viii) optionally-substituted 5- to 10-membered unsaturatedaliphatic heterocyclyl group, the (ix) optionally-substituted 6- to10-membered aryl group, and the (x) optionally-substituted 5- to10-membered heteroaryl group are independently one or more substituentsselected independently from the group consisting of hydroxy group,methoxy group, ethoxy group, carboxyl group, carbamoyl group which maybe substituted with one or two the same or different C₁₋₃ alkyl, andamino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl,

Y is carbon atom or CH, and

Z is carbon atom, CH, or nitrogen atom, provided that the combination ofX, Y, and Z should be any one of chemically-possible selections.

The compounds of formula (1) in Term 1 include those of formula (1′).The groups of formulae (2) and (3) in Term 1 include those of formulae(2′) and (3′).

Term 3

The compound of Term 2 or a pharmaceutically acceptable salt thereof,wherein R² is hydrogen atom.

Term 4

The compound of Term 2 or 3 or a pharmaceutically acceptable saltthereof, wherein R³ is (i) hydrogen atom, (ii) C₁₋₃ alkyl group, or (v)3- to 6-membered cycloalkyl group.

Term 5

The compound of any one of Terms 2-4 or a pharmaceutically acceptablesalt thereof, wherein R³ is hydrogen atom or methyl group.

Term 6

The compound of any one of Terms 2-5 or a pharmaceutically acceptablesalt thereof, wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkyl group, or(v) 3- to 6-membered cycloalkyl group.

Term 7

The compound of any one of Terms 2-6 or a pharmaceutically acceptablesalt thereof, wherein R⁴ is methyl group.

Term 8

The compound of any one of Terms 2-7 or a pharmaceutically acceptablesalt thereof, wherein

R¹ is (i) hydrogen atom, or (ii) optionally-substituted C₁₋₆ alkylgroup,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thegroups of formulae (4)-(6).

Term 9

The compound of any one of Terms 2-7 or a pharmaceutically acceptablesalt thereof, wherein

R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₃ alkyl group,

(iii) optionally-substituted C₂₋₄ alkenyl group,

(iv) optionally-substituted C₂₋₄ alkynyl group,

(v) optionally-substituted 3- to 6-membered cycloalkyl group,

(vi) optionally-substituted 4- to 6-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 6-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₃ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus),

the substituent (s) of the (iii) optionally-substituted C₂₋₄ alkenylgroup, and the (iv) optionally-substituted C₂₋₄ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 6-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 6-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 6-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group.

Term 10

The compound of any one of Terms 2-9 or a pharmaceutically acceptablesalt thereof, wherein

R¹ is (i) hydrogen atom, or (11) optionally-substituted C₁₋₃ alkylgroup,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₃ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus).

Term 11

The compound of any one of Terms 2-10 or a pharmaceutically acceptablesalt thereof, wherein

R¹ is hydrogen atom, or the group of formula (6),

in formula (6), L³ is C(O), R⁹ is amino acid group (which binds to L³ atits N terminus).

Term 12

The compound of any one of Terms 2-11 or a pharmaceutically acceptablesalt thereof, wherein Ring A is the group of formula (2′).

Term 13

The compound of Term 12 or a pharmaceutically acceptable salt thereof,wherein the part of X

Y

Z in formula (2′) is N═C—CH, N═C—N, NR⁴—C═C, NR⁴—CH—N, or NR⁴—CH—CH.

Term 14

The compound of Term 12 or 13 or a pharmaceutically acceptable saltthereof, wherein the part of X

Y

Z in formula (2′) is N═C—N or NR⁴—C═C.

Term 15

The compound of any one of Terms 2-11 or a pharmaceutically acceptablesalt thereof, wherein Ring A is the group of formula (3′).

Term 16

The compound of Term 15 or a pharmaceutically acceptable salt thereof,wherein the part of X

Y

Z in formula (3′) is N═C—CH, N═C—N, NR⁴—C═C, NR⁴—CH—N, NR⁴—CH—CH, O—C═C,O—CH—N, or O—CH—CH.

Term 17

The compound of Term 15 or 16 or a pharmaceutically acceptable saltthereof, wherein the part of X

Y

Z in formula (3′) is NR⁴—C═C or O—C═C.

Term 18

The compound of Term 2 or a pharmaceutically acceptable salt thereof,wherein

R¹ is

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, 2, 3, 4, or 5, R⁷ is amino acid group (whichbinds to C(O) at its N terminus), or peptide consisting of 2-3 aminoacid residues (which binds to C(O) at its N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, amino acid group (which binds to L² at itsN terminus), or peptide consisting of 2-3 amino acid residues (whichbinds to L² at its N terminus),

in formula (6), L³ is CH₂ or C(O), R⁹ is hydroxy group, amino groupwhich may be substituted with one or two the same or different C₁₋₃alkyl, amino acid group (which binds to L³ at its N terminus), orpeptide consisting of 2-3 amino acid residues (which binds to L³ at itsN terminus),

the substituent (s) of the (iii) optionally-substituted C₂₋₆ alkenylgroup, and the (iv) optionally-substituted C₂₋₆ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 8-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group;

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is N═C—N or NR⁴—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group,

when Ring A is a group of formula (3′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is NR⁴—C═C or O—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group.

Term 19

The compound of Term 2 or 18 or a pharmaceutically acceptable saltthereof, wherein

R¹ is (i) hydrogen atom, or (ii) optionally-substituted C₁₋₆ alkylgroup,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, 2, 3, 4, or 5, R⁷ is amino acid group (whichbinds to C(O) at its N terminus), or peptide consisting of 2-3 aminoacid residues (which binds to C(O) at its N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, amino acid group (which binds to L² at itsN terminus), or peptide consisting of 2-3 amino acid residues (whichbinds to L² at its N terminus),

in formula (6), L³ is CH₂ or C(O), R⁹ is hydroxy group, amino groupwhich may be substituted with one or two the same or different C₁₋₃alkyl, amino acid group (which binds to L³ at its N terminus), orpeptide consisting of 2-3 amino acid residues (which binds to L³ at itsN terminus);

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is N═C—N or NR⁴—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group,

when Ring A is a group of formula (3′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is NR⁴—C═C or O—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group.

Term 20

The compound of Term 2 or 18 or a pharmaceutically acceptable saltthereof, wherein

R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₃ alkyl group,

(iii) optionally-substituted C₂₋₄ alkenyl group,

(iv) optionally-substituted C₂₋₄ alkynyl group,

(v) optionally-substituted 3- to 6-membered cycloalkyl group,

(vi) optionally-substituted 4- to 6-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 6-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₃ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus),

the substituent (s) of the (iii) optionally-substituted C₂₋₄ alkenylgroup, and the (iv) optionally-substituted C₂₋₄ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 6-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 6-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 6-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group;

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is N═C—N or NR⁴—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group,

when Ring A is a group of formula (3′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is NR⁴—C═C or O—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group.

Term 21

The compound of any one of Terms 2 and 18-20 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is (i) hydrogen atom, or (ii) optionally-substituted C₁₋₃ alkylgroup,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₃ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus);

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is N═C—N or NR⁴—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group,

when Ring A is a group of formula (3′), R³ is (i) hydrogen atom, (ii)C₁₋₃ alkyl group, or (v) 3- to 6-membered cycloalkyl group, the part ofX

Y

Z is NR⁴—C═C or O—C═C wherein R⁴ is (i) hydrogen atom, (ii) C₁₋₃ alkylgroup, or (v) 3- to 6-membered cycloalkyl group.

Term 22

The compound of Term 2 or 18 or a pharmaceutically acceptable saltthereof, wherein

R¹ is

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, 2, 3, 4, or 5, R⁷ is amino acid group (whichbinds to C(O) at its N terminus), or peptide consisting of 2-3 aminoacid residues (which binds to C(O) at its N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, amino acid group (which binds to L² at itsN terminus), or peptide consisting of 2-3 amino acid residues (whichbinds to L² at its N terminus),

in formula (6), L³ is CH₂ or C(O), R⁹ is hydroxy group, amino groupwhich may be substituted with one or two the same or different C₁₋₃alkyl, amino acid group (which binds to L³ at its N terminus), orpeptide consisting of 2-3 amino acid residues (which binds to L³ at itsN terminus),

the substituent (s) of the (iii) optionally-substituted C₂₋₆ alkenylgroup, and the (iv) optionally-substituted C₂₋₆ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 8-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group;

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is N═C—N or NCH₃—C═C,

when Ring A is a group of formula (3′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is NCH₃—C═C Or O—C═C.

Term 23

The compound of any one of Terms 2, 18, 19, and 22 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is (i) hydrogen atom, or (11) optionally-substituted C₁₋₆ alkylgroup,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, 2, 3, 4, or 5, R⁷ is amino acid group (whichbinds to C(O) at its N terminus), or peptide consisting of 2-3 aminoacid residues (which binds to C(O) at its N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, amino acid group (which binds to L² at itsN terminus), or peptide consisting of 2-3 amino acid residues (whichbinds to L² at its N terminus),

in formula (6), L³ is CH₂ or C(O), R⁹ is hydroxy group, amino groupwhich may be substituted with one or two the same or different C₁₋₃alkyl, amino acid group (which binds to L³ at its N terminus), orpeptide consisting of 2-3 amino acid residues (which binds to L³ at itsN terminus);

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is N═C—N or NCH₃—C═C,

when Ring A is a group of formula (3′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is NCH₃—C═C or O—C═C.

Term 24

The compound of any one of Terms 2, 18, 20, and 22 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₃ alkyl group,

(iii) optionally-substituted C₂₋₄ alkenyl group,

(iv) optionally-substituted C₂₋₄ alkynyl group,

(v) optionally-substituted 3- to 6-membered cycloalkyl group,

(vi) optionally-substituted 4- to 6-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 6-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent (s) of the (ii) optionally-substituted C₁₋₃alkyl group is one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent (s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus),

the substituent (s) of the (iii) optionally-substituted C₂₋₄ alkenylgroup, and the (iv) optionally-substituted C₂₋₄ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 6-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 6-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 6-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group;

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is N═C—N or NCH₃—C═C,

when Ring A is a group of formula (3′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is NCH₃—C═C Or O—C═C.

Term 25

The compound of any one of Terms 2 and 18-24 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is (i) hydrogen atom, or (ii) optionally-substituted C₁₋₃ alkylgroup,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₃ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus);

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is N═C—N or NCH₃—C═C,

when Ring A is a group of formula (3′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is NCH₃—C═C or O—C═C.

Term 26

The compound of any one of Terms 2, 18-25 or a pharmaceuticallyacceptable salt thereof, wherein

R¹ is, hydrogen atom, or the group of formula (6),

in formula (6), L³ is C(O), R⁹ is amino acid group (which binds to L³ atits N terminus);

R² is hydrogen atom; and

Ring A is a group of formula (2′) or (3′),

when Ring A is a group of formula (2′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is N═C—N or NCH₃—C═C,

when Ring A is a group of formula (3′), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is NCH₃—C═C or O—C═C.

Term 27

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof which is represented by formula (7):

wherein

Ring B is a group of formula (8), (9), or (10);

R¹ is

(i) hydrogen atom,

(ii) C₁₋₃ alkyl group

-   -   which may be substituted with one or more substituents selected        independently from the group consisting of hydroxy group,        methoxy group, ethoxy group, carboxyl group, carbamoyl group        (which may be substituted with one or two the same or different        C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ are independently hydrogen        atom, C₁₋₃ alkyl group, carboxylmethyl group, 2-hydroxyethyl        group, or 2-aminoethyl group), 3- to 6-membered cycloalkyl group        (which may be substituted with one or more substituents selected        independently from the group consisting of amino group which may        be substituted with one or two the same or different C₁₋₃ alkyl,        C₁₋₃ alkyl group, hydroxy group, and carboxyl group), 4- to        6-membered saturated aliphatic heterocyclyl group (which may be        substituted with one or more substituents selected independently        from the group consisting of amino group which may be        substituted with one or two the same or different C₁₋₃ alkyl,        C₁₋₃ alkyl group, hydroxy group, and carboxyl group), and 5- to        10-membered heteroaryl group (which may be substituted with one        or more substituents selected independently from the group        consisting of amino group which may be substituted with one or        two the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy        group, and carboxyl group),

(iii) the group of formula (4):

wherein m is 1, 2, 3, 4, or 5, R⁷ is C₁₋₃ alkoxy group, amino acid group(which binds to C(O) at its N terminus), and peptide consisting of 2-3amino acid residues (which binds to C(O) at its N terminus),

(iv) the group of formula (5):

R⁸-L²-(CH₂CH₂O)_(q)CH₂CH₂

  (5)

wherein q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ is hydroxygroup, C₁₋₃ alkoxy group, amino group which may be substituted with oneor two the same or different C₁₋₃ alkyl, amino acid group (which bindsto L² at its N terminus), or peptide consisting of 2-3 amino acidresidues (which binds to L² at its N terminus), or

(v) the group of formula (6):

wherein L³ is CH₂ or C(O), and R⁹ is hydroxy group, C₁₋₃ alkoxy group,amino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl, amino acid group (which binds to L³ at its Nterminus), or peptide consisting of 2-3 amino acid residues (which bindsto L³ at its N terminus);

X¹ is O or NR¹⁴; and

R¹³ and R¹⁴ are independently hydrogen atom, C₁₋₃ alkyl group, or 3- to6-membered cycloalkyl group.

Term 28

The compound of Term 27 or a pharmaceutically acceptable salt thereof,wherein Ring B is the group of formula (8).

Term 29

The compound of Term 27 or 28 or a pharmaceutically acceptable saltthereof, wherein R¹ is the group of formula (4), (5), or (6).

Term 30

The compound of any one of Terms 27-29 or a pharmaceutically acceptablesalt thereof, wherein L² and L³ are C(O).

Term 31

The compound of any one of Terms 27-29 or a pharmaceutically acceptablesalt thereof, wherein R¹ is the group of formula (4).

Term 32

The compound of any one of Terms 27-30 or a pharmaceutically acceptablesalt thereof, wherein R¹ is the group of formula (6).

Term 33

The compound of any one of Terms 27-32 or a pharmaceutically acceptablesalt thereof, wherein R⁷, R⁸, or R⁹ is amino acid group (which binds toC(O), L², or L³ at its N terminus).

Term 34

The compound of any one of Terms 27-33 or a pharmaceutically acceptablesalt thereof, wherein R⁷, R⁸, or R⁹ is L-glutamic acid (which binds toC(O), L², or L³ at its N terminus).

Term 35

The compound of any one of Terms 27-34 or a pharmaceutically acceptablesalt thereof, wherein R¹³ is hydrogen atom.

Term 36

The compound of any one of Terms 27-35 or a pharmaceutically acceptablesalt thereof, wherein X¹ is NR¹⁴.

Term 37

The compound of any one of Terms 27-36 or a pharmaceutically acceptablesalt thereof wherein R¹⁴ is methyl group.

Term 38

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the following compounds:

-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 1),-   prop-2-yn-1-yl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 2),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 3),-   N²-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine    (Example 4),-   N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic    acid (Example 5),-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-N-(prop-2-yn-1-yl)-4H-chromene-5-carboxamide    (Example 6),-   3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 7),-   N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 8),-   6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylic    acid (Example 9),-   prop-2-yn-1-yl    6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylate    (Example 10),-   N-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamic    acid (Example 11),-   N²-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-arginine    (Example 12),-   3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 13),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 14),-   N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 15),-   3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 16),-   N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 17),-   N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 18),-   N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 19),-   3-[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoic    acid (Example 20),-   N-{3-[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoyl}-L-glutamic    acid (Example 21),-   2,2′-{[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethyl]imino}-diacetic    acid (Example 22),-   2,3-dihydroxypropyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 23),-   (trans-4-aminocyclohexyl)methyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 24),-   (1,4-dimethylpiperazin-2-yl)methyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 25),-   (1-methyl-1H-imidazol-2-yl)methyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 26),-   0-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-homoserine    (Example 27),-   2-(3-hydroxypyrrolidin-1-yl)ethyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 28),-   14-hydroxy-3,6,9,12-tetraoxatetradec-1-yl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 29), and-   2-amino-2-oxoethyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 30).

Term 39

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the following compounds:

-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 1),-   prop-2-yn-1-yl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 2),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 3),-   N²-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine    (Example 4),-   N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic    acid (Example 5),-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-N-(prop-2-yn-1-yl)-4H-chromene-5-carboxamide    (Example 6),-   3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 7),-   N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 8),-   6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylic    acid (Example 9),-   prop-2-yn-1-yl    6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylate    (Example 10),-   N-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamic    acid (Example 11),-   N²-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-arginine    (Example 12),-   3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 13),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 14),-   N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 15),-   3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 16),-   N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 17),-   N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 18), and-   N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 19).

Term 40

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the

-   following compounds:-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 1),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 3),-   N²-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine    (Example 4),-   N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic    acid (Example 5),-   3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 7),-   N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 8),-   6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylic    acid (Example 9),-   N-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamic    acid (Example 11),-   N²-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-arginine    (Example 12),-   3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 13),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 14),-   N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 15),-   3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 16),-   N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 17),-   N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 18), and-   N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 19).

Term 41

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the

-   following compounds:-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid-   (Example 1),-   prop-2-yn-1-yl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 2),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 3),-   N²-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine    (Example 4),-   N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic    acid (Example 5),-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-N-(prop-2-yn-1-yl)-4H-chromene-5-carboxamide    (Example 6),-   3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 7),-   N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 8),-   3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 16),-   N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 17),-   N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 18),-   N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 19),-   3-[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoic    acid (Example 20),-   N-{3-[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoyl}-L-glutamic    acid (Example 21),-   2,2′-{[2-({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethyl]imino}-diacetic    acid (Example 22),-   2,3-dihydroxypropyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 23),-   (trans-4-aminocyclohexyl)methyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 24),-   (1,4-dimethylpiperazin-2-yl)methyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 25),-   (1-methyl-1H-imidazol-2-yl)methyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 26),-   0-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-homoserine    (Example 27),-   2-(3-hydroxypyrrolidin-1-yl)ethyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 28),-   14-hydroxy-3,6,9,12-tetraoxatetradec-1-yl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 29), and-   2-amino-2-oxoethyl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 30).

Term 42

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the

-   following compounds:-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid-   (Example 1),-   prop-2-yn-1-yl    3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate    (Example 2),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 3),-   N²-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine    (Example 4),-   N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic    acid (Example 5),-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-N-(prop-2-yn-1-yl)-4H-chromene-5-carboxamide    (Example 6),-   3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 7),-   N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 8),-   3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 16),-   N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 17),-   N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 18), and-   N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 19).

Term 43

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the

-   following compounds:-   3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid-   (Example 1),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 3),-   N²-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine    (Example 4),-   N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamic    acid (Example 5),-   3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 7),-   N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 8),-   3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid (Example 16),-   N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 17),-   N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 18), and-   N-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamic    acid (Example 19).

Term 44

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the

-   following compounds:-   6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylic    acid (Example 9),-   prop-2-yn-1-yl    6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylate    (Example 10),-   N-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamic    acid (Example 11),-   N²-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-arginine    (Example 12),-   3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid-   (Example 13),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 14), and-   N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 15).

Term 45

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, which is selected from the

-   following compounds:-   6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylic    acid (Example 9),-   N-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,    4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamic    acid (Example 11),-   N²-{[4-({[(6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-arginine    (Example 12),-   3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylic    acid-   (Example 13),-   N-({4-[({[3-(6,7-dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 14), and-   N-({4-[({[3-(6,7-dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamic    acid (Example 15).

Term 46

A pharmaceutical composition comprising the compound of any one of Terms1-45 or a pharmaceutically acceptable salt thereof.

Term 47

A semaphorin inhibitor comprising the compound of any one of Terms 1-45or a pharmaceutically acceptable salt thereof as an active ingredient.

Term 48

The semaphorin inhibitor of Term 47, wherein the semaphorin is class 3semaphorins.

Term 49

The semaphorin inhibitor of Term 48, wherein the class 3 semaphorins issemaphorin 3A.

Term 50

An inhibitor for a nerve outgrowth repelling factor comprising thecompound of any one of Terms 1-45 or a pharmaceutically acceptable saltthereof as an active ingredient.

Term 51

A medicament having suppressing action on the growth cone collapseactivity and/or suppressing action on the nerve outgrowth inhibitoryactivity in a collagen gel, comprising the compound of any one of Terms1-45 or a pharmaceutically acceptable salt thereof as an activeingredient.

Term 52

A nerve regeneration promoter comprising the compound of any one ofTerms 1-45 or a pharmaceutically acceptable salt thereof as an activeingredient.

Term 53

A medicament for treating and/or preventing a disease associated withneurodegeneration or neurological disorder, comprising the compound ofany one of Terms 1-45 or a pharmaceutically acceptable salt thereof asan active ingredient.

Term 54

A medicament for treating and/or preventing a neurological diseaseassociated with ischemic damage, comprising the compound of any one ofTerms 1-45 or a pharmaceutically acceptable salt thereof as an activeingredient.

Term 55

The medicament of Term 54, wherein the neurological disease associatedwith ischemic damage is retinal neurological disorder caused by ischemiaor ischemic cerebrovascular disease.

Term 56

The medicament of Term 55, wherein the retinal neurological disorder isglaucoma, central retinal artery occlusion, central branch retinalartery occlusion, central retinal vein occlusion, central branch retinalvein occlusion, ischemic optic neuropathy, diabetic retinopathy, maculardegeneration, or retinopathy of prematurity.

Term 57

The medicament of Term 55, wherein the ischemic cerebrovascular diseaseis cerebral emboli, transient cerebral ischemia, subclavian stealsyndrome, Wallenberg's syndrome (lateral medullary syndrome), cerebralthrombosis, lacunar infarct, reversible ischemic neurological deficit,cerebral infarct, moyamoya disease (spontaneous occlusion of the circleof Willis), cerebral hypoxia, sinus thrombosis, or postoperative spinalcord ischemia.

Term 58

A medicament for treating and/or preventing corneal disease, comprisingthe compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof as an active ingredient.

Term 59

The medicament of Term 58, wherein the corneal disease is dry eye,keratitis, leukoma, corneal infection, corneal degeneration, cornealdystrophy, corneal stromal dystrophy, bullous keratopathy, keratoconus,corneal endothelial decompensation, corneal ulcer, nerve-paralytickeratopathy, diabetic keratopathy, chemical ocular injury or cornealburn.

Term 60

The medicament of Term 59, wherein the corneal disease is dry eye,keratitis, bullous keratopathy, corneal ulcer, nerve-paralytickeratopathy, or diabetic keratopathy.

Term 61

The medicament of Term 59, wherein the corneal disease is dry eye.

Term 62

The medicament of any one of Terms 58-61, wherein the corneal disease isa disease associated with neurodegeneration or neurological disorder.

Term 63

A medicament for treating and/or preventing a disease associated withdegeneration and damage in central nerve and peripheral nerve,comprising the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof as an active ingredient.

Term 64

A medicament for treating and/or preventing dysosmia, traumaticneurological disorder, cerebral-infarct neurological disorder, facialpalsy, diabetic neurosis, glaucoma, retinitis pigmentosa, dry eye,Alzheimer's disease, Parkinson's disease, neurodegenerative disease,muscular dysgenic lateral sclerosis, amyotrophic lateral sclerosis,Huntington's disease, cerebral infarct, or traumatic neurodegenerativedisease, comprising the compound of any one of Terms 1-45 or apharmaceutically acceptable salt thereof as an active ingredient.

Term 65

A medicament for treating and/or preventing dry eye, comprising thecompound of any one of Terms 1-45 or a pharmaceutically acceptable saltthereof as an active ingredient.

Term 66

A method for treating and/or preventing a disease associated withneurodegeneration or neurological disorder, comprising administering atherapeutically effective amount of the compound of any one of Terms1-45 or a pharmaceutically acceptable salt thereof to a patient in needthereof.

Term 67

A method for treating and/or preventing a neurological diseaseassociated with ischemic damage, comprising administering atherapeutically effective amount of the compound of any one of Terms1-45 or a pharmaceutically acceptable salt thereof to a patient in needthereof.

Term 68

The method of Term 67, wherein the neurological disease associated withischemic damage is retinal neurological disorder caused by ischemia orischemic cerebrovascular disease.

Term 69

The method of Term 68, wherein the retinal neurological disorder isglaucoma, central retinal artery occlusion, central branch retinalartery occlusion, central retinal vein occlusion, central branch retinalvein occlusion, ischemic optic neuropathy, diabetic retinopathy, maculardegeneration, or retinopathy of prematurity.

Term 70

The method of Term 68, wherein the ischemic cerebrovascular disease iscerebral emboli, transient cerebral ischemia, subclavian steal syndrome,Wallenberg's syndrome (lateral medullary syndrome), cerebral thrombosis,lacunar infarct, reversible ischemic neurological deficit, cerebralinfarct, moyamoya disease (spontaneous occlusion of the circle ofWillis), cerebral hypoxia, sinus thrombosis, or postoperative spinalcord ischemia.

Term 71

A method for treating and/or preventing corneal disease, comprisingadministering a therapeutically effective amount of the compound of anyone of Terms 1-45 or a pharmaceutically acceptable salt thereof to apatient in need thereof.

Term 72

The method of Term 71, wherein the corneal disease is dry eye,keratitis, leukoma, corneal infection, corneal degeneration, cornealdystrophy, corneal stromal dystrophy, bullous keratopathy, keratoconus,corneal endothelial decompensation, corneal ulcer, nerve-paralytickeratopathy, diabetic keratopathy, chemical ocular injury, or cornealburn.

Term 73

The method of Term 72, wherein the corneal disease is dry eye,keratitis, bullous keratopathy, corneal ulcer, nerve-paralytickeratopathy, or diabetic keratopathy.

Term 74

The method of Term 72, wherein the corneal disease is dry eye.

Term 75

The method of any one of Terms 71-74, wherein the corneal disease is adisease associated with neurodegeneration or neurological disorder.

Term 76

A method for treating and/or preventing a disease associated withdegeneration and damage in central nerve and peripheral nerve,comprising administering a therapeutically effective amount of thecompound of any one of Terms 1-45 or a pharmaceutically acceptable saltthereof to a patient in need thereof.

Term 77

A method for treating and/or preventing dysosmia, traumatic neurologicaldisorder, cerebral-infarct neurological disorder, facial palsy, diabeticneurosis, glaucoma, retinitis pigmentosa, dry eye, Alzheimer's disease,Parkinson's disease, neurodegenerative disease, muscular dysgeniclateral sclerosis, amyotrophic lateral sclerosis, Huntington's disease,cerebral infarct, or traumatic neurodegenerative disease, comprisingadministering a therapeutically effective amount of the compound of anyone of Terms 1-45 or a pharmaceutically acceptable salt thereof to apatient in need thereof.

Term 78

A method for treating and/or preventing dry eye, comprisingadministering a therapeutically effective amount of the compound of anyone of Terms 1-45 or a pharmaceutically acceptable salt thereof to apatient in need thereof.

Term 79

Use of the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for treatingand/or preventing a disease associated with neurodegeneration orneurological disorder.

Term 80

Use of the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for treatingand/or preventing a neurological disease associated with ischemicdamage.

Term 81

The use of Term 80, wherein the neurological disease associated withischemic damage is retinal neurological disorder caused by ischemia, orischemic cerebrovascular disease.

Term 82

The use of Term 81, wherein the retinal neurological disorder isglaucoma, central retinal artery occlusion, central branch retinalartery occlusion, central retinal vein occlusion, central branch retinalvein occlusion, ischemic optic neuropathy, diabetic retinopathy, maculardegeneration, or retinopathy of prematurity.

Term 83

The use of Term 81, wherein the ischemic cerebrovascular disease iscerebral emboli, transient cerebral ischemia, subclavian steal syndrome,Wallenberg's syndrome (lateral medullary syndrome), cerebral thrombosis,lacunar infarct, reversible ischemic neurological deficit, cerebralinfarct, moyamoya disease (spontaneous occlusion of the circle ofWillis), cerebral hypoxia, sinus thrombosis, or postoperative spinalcord ischemia.

Term 84

Use of the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for treatingand/or preventing corneal disease.

Term 85

The use of Term 84, wherein the corneal disease is dry eye, keratitis,leukoma, corneal infection, corneal degeneration, corneal dystrophy,corneal stromal dystrophy, bullous keratopathy, keratoconus, cornealendothelial decompensation, corneal ulcer, nerve-paralytic keratopathy,diabetic keratopathy, chemical ocular injury, or corneal burn.

Term 86

The use of Term 85, wherein the corneal disease is dry eye, keratitis,bullous keratopathy, corneal ulcer, nerve-paralytic keratopathy, ordiabetic keratopathy.

Term 87

The use of Term 85, wherein the corneal disease is dry eye.

Term 88

The use of any one of Terms 84-87, wherein the corneal disease is adisease associated with neurodegeneration or neurological disorder.

Term 89

Use of the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for treatingand/or preventing a disease associated with degeneration and damage incentral nerve and peripheral nerve.

Term 90

Use of the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for treatingor preventing dysosmia, traumatic neurological disorder,cerebral-infarct neurological disorder, facial palsy, diabetic neurosis,glaucoma, retinitis pigmentosa, dry eye, Alzheimer's disease,Parkinson's disease, neurodegenerative disease, muscular dysgeniclateral sclerosis, amyotrophic lateral sclerosis, Huntington's disease,cerebral infarct, or traumatic neurodegenerative disease.

Term 91

Use of the compound of any one of Terms 1-45 or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament for treatingand/or preventing dry eye.

Term 92

The compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof, in use for treating and/or preventing a disease associatedwith neurodegeneration or neurological disorder.

Term 93

The compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof, in use for treating and/or preventing a neurologicaldisease associated with ischemic damage.

Term 94

The medicament of Term 93, wherein the neurological disease associatedwith ischemic damage is retinal neurological disorder caused by ischemiaor ischemic cerebrovascular disease.

Term 95

The compound of Term 94 or a pharmaceutically acceptable salt thereof,wherein the retinal neurological disorder is glaucoma, central retinalartery occlusion, central branch retinal artery occlusion, centralretinal vein occlusion, central branch retinal vein occlusion, ischemicoptic neuropathy, diabetic retinopathy, macular degeneration, orretinopathy of prematurity.

Term 96

The compound of Term 94 or a pharmaceutically acceptable salt thereof,wherein the ischemic cerebrovascular disease is cerebral emboli,transient cerebral ischemia, subclavian steal syndrome, Wallenberg'ssyndrome (lateral medullary syndrome), cerebral thrombosis, lacunarinfarct, reversible ischemic neurological deficit, cerebral infarct,moyamoya disease (spontaneous occlusion of the circle of Willis),cerebral hypoxia, sinus thrombosis, or postoperative spinal cordischemia.

Term 97

The compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof, in use for treating and/or preventing corneal disease.

Term 98

The compound of Term 97 or a pharmaceutically acceptable salt thereof,wherein the corneal disease is dry eye, keratitis, leukoma, cornealinfection, corneal degeneration, corneal dystrophy, corneal stromaldystrophy, bullous keratopathy, keratoconus, corneal endothelialdecompensation, corneal ulcer, nerve-paralytic keratopathy, diabetickeratopathy, chemical ocular injury, or corneal burn.

Term 99

The compound of Term 98 or a pharmaceutically acceptable salt thereof,wherein the corneal disease is dry eye, keratitis, bullous keratopathy,corneal ulcer, nerve-paralytic keratopathy, or diabetic keratopathy.

Term 100

The compound of Term 98 or a pharmaceutically acceptable salt thereof,wherein the corneal disease is dry eye.

Term 101

The compound of any one of Terms 97-100 or a pharmaceutically acceptablesalt thereof, wherein the corneal disease is a disease associated withneurodegeneration or neurological disorder.

Term 102

The compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof, in use for treating and/or preventing a disease associatedwith degeneration and damage in central nerve and peripheral nerve.

Term 103

The compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof, in use for treating and/or preventing dysosmia, traumaticneurological disorder, cerebral-infarct neurological disorder, facialpalsy, diabetic neurosis, glaucoma, retinitis pigmentosa, dry eye,Alzheimer's disease, Parkinson's disease, neurodegenerative disease,muscular dysgenic lateral sclerosis, amyotrophic lateral sclerosis,Huntington's disease, cerebral infarct, or traumatic neurodegenerativedisease.

Term 104

The compound of any one of Terms 1-45 or a pharmaceutically acceptablesalt thereof, in use for treating and/or preventing dry eye.

Effect of Invention

The present invention provides the compound of formula (1) or apharmaceutically acceptable salt thereof. The compound or apharmaceutically acceptable salt thereof has a semaphorin inhibitoryactivity and it is useful as a medicament for treating or preventingneuropathic disease, neurodegenerative disease, neurological diseaseassociated with ischemic deficit, and corneal disease.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows results of the evaluation on the pharmacological action forcorneal disorder, in which hyaluronic acid, diquafosol sodium, and thecompound of Example 3 were administered to the dry eye-model rat in Test3.

FIG. 2 shows results of the evaluation on the pharmacological action fordysfunction of corneal nerves, in which hyaluronic acid, diquafosolsodium, and the compound of Example 3 were administered to the dryeye-model rat in Test 4.

FIG. 3 shows results of the evaluation on the pharmacological action forcorneal disorder, in which 0.01%, 0.1%, and 1% the ophthalmic solutionsof the compound of Example 19 were administered to the dry eye-model ratin Test 5.

DESCRIPTION OF EMBODIMENTS

Each preferable embodiment in the present invention mentioned below maybe combined with another preferable embodiment, or its correspondentexample defined in the above Terms 1 to 93.

The “one or more” in one or more substituents, one or more alkyl groups,and the like which are used in defining the substituents in the presentinvention includes, for example, 1-7, 1-6, 1-5, 1-4, 1-3, and 1-2, whichmeans that substituents may be used within the chemically-possiblenumber. The “1-plural” also has the same meaning. When substituted withplural substituents, the substituents may be the same or a combinationof any different substituents. In case of three or more substituents,the substituents may be all the same, partially the same, or alldifferent.

The compound of the present invention may be in a form of hydrate and/orsolvate, thus the compound of formula (1) or a pharmaceuticallyacceptable salt thereof encompasses such hydrate and/or solvate.

In addition, the compound of formula (1) in which any one or more ¹Hatoms are replaced by ²H(D) atoms (deuterium form) is within the scopeof the present invention of formula (1).

There may exist a polymorphism in a crystal of the compound of formula(1) or a pharmaceutically acceptable salt thereof, and hence suchcrystal polymorphism is also within the scope of the present invention.

The “halogen atom” used herein means the atoms belonging to group 17 inthe periodic table, including, for example, fluorine, chlorine, bromineand iodine. In addition, the “halo” in “haloalkyl group”, “haloalkoxy(haloalkyloxy) group”, and the like means fluoro, chloro, bromo, andiodo, and the above exemplified groups mean alkyl or alkoxy group whichis substituted with one or more the same or different halogen atoms.

The “alkyl group” used herein means straight or branched chain saturatedhydrocarbon group having 1 to 10 carbon atoms. The alkyl grouppreferably includes C₁₋₆ alkyl group, for example, methyl group, ethylgroup, propyl group (1-propyl group) and isopropyl group (2-propylgroup), butyl group (1-butyl group), sec-butyl group (2-butyl group),isobutyl group (2-methyl-1-propyl group), t-butyl group(2-methyl-2-propyl group), pentyl group (1-pentyl group), and hexylgroup (1-hexyl group). The alkyl group more preferably includes C₁₋₃alkyl group, for example, methyl group, ethyl group, propyl group(1-propyl group), and isopropyl group (2-propyl group). Even morepreferably, the alkyl group is methyl group or ethyl group.

The alkyl moiety in “haloalkyl group”, “alkoxy (alkyloxy) group”,“haloalkoxy (haloalkyloxy) group”, “alkoxycarbonyl group”,“alkylcarbonyl group”, “alkylcarbonyloxy group”, “alkylthio group”,“alkylsulfonyl group”, and the like used herein is as defined in theabove “alkyl group”.

The “alkenyl group” used herein means straight or branched chainunsaturated hydrocarbon group having 2 to 10 carbon atoms and at leastone double bond. The alkenyl group preferably includes C₂₋₆ alkenylgroup, for example, vinyl group, 1-propenyl group, 2-propenyl group,1-methylvinyl group, 1-butenyl group, 1-ethylvinyl group,1-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group,2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group,and 1-hexenyl group. The alkenyl group more preferably includes C₂₋₄alkenyl group, for example, vinyl group, 1-propenyl group, 2-propenylgroup, and 1-methylvinyl group. Even more preferably, the alkenyl groupis vinyl group, 1-propenyl group, 2-propenyl group, or 1-methylvinylgroup. The number of the double bonds in the alkenyl group may be one ortwo.

The “alkynyl group” used herein means straight or branched chainunsaturated hydrocarbon group having 2 to 10 carbon atoms and at leastone triple bond. The alkynyl group preferably includes C₂₋₆ alkynylgroup, for example, ethynyl group, 1-propynyl group, 2-propynyl group,1-butynyl group, 1-methyl-2-propynyl group, 3-butynyl group, 1-pentynylgroup, and 1-hexynyl group. The alkynyl group more preferably includes“C₂₋₄ alkynyl group”, for example, ethynyl group, 1-propynyl group, and2-propynyl group. Even more preferably, the alkynyl group is ethynylgroup, 1-propynyl group, or 2-propynyl group.

The “cycloalkyl group” used herein means mono-, bi-, or tri-cyclicsaturated hydrocarbon having 3 to 14 carbon atoms. The cycloalkyl grouppreferably includes 3- to 8-membered cycloalkyl group which may be mono-or bi-cyclic group, for example, cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctylgroup. The cycloalkyl group more preferably includes mono-cyclic 3- to6-membered cycloalkyl group, for example, cyclopropyl group, cyclobutylgroup, cyclopentyl group, and cyclohexyl group. Even more preferably,the cycloalkyl group is cyclopropyl group or cyclobutyl group.

The “cycloalkenyl group” used herein means mono-, bi-, or tri-cyclicunsaturated hydrocarbon group having 4 to 14 carbon atoms and at leastone double bond. The position of the double bond in the ring is notlimited. The cycloalkenyl group preferably includes 4- to 8-memberedcycloalkenyl group which may be mono- or bi-cyclic group, for example,cyclobutenyl group, cyclopentenyl group, cyclohexenyl group,cycloheptenyl group, and cyclooctenyl group. The cycloalkenyl group morepreferably includes 4- to 6-membered cycloalkenyl group, for example,cyclobutenyl group, and cyclopentenyl group.

The “saturated aliphatic heterocyclyl group” used herein means mono-,bi-, or tri-cyclic saturated aliphatic heterocyclyl group having 1 to 3heteroatoms selected independently from the group consisting of nitrogenatom, oxygen atom, and sulfur atom and 2-12 carbon atoms. Each maximumnumber of oxygen atom and sulfur atom in the saturated aliphaticheterocyclyl group is two, and the position of the heteroatoms in thering is not limited as long as it is chemically stable. The saturatedaliphatic heterocyclyl group preferably includes 4- to 8-memberedsaturated aliphatic heterocyclyl group which may be mono- or bi-cyclicgroup. The saturated aliphatic heterocyclyl group more preferablyincludes mono-cyclic 4- to 6-membered saturated aliphatic heterocyclylgroup, for example, azetidinyl group, pyrrolidinyl group, piperidylgroup, piperidino group, piperazinyl group, tetrahydrofuryl group,tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group,morpholino group, thiomorpholinyl group, and 1,4-dioxanyl group.

The “unsaturated aliphatic heterocyclyl group” used herein means mono-,bi-, or tri-cyclic unsaturated aliphatic heterocyclyl group having 1 to3 heteroatoms selected independently from the group consisting ofnitrogen atom, oxygen atom, and sulfur atom, 1-3 double bonds, and 3-12carbon atoms, which does not include aromatic heterocyclyl groups, butincludes a fused ring group of aliphatic heterocycle and aromatic ring.Each maximum number of oxygen atom and sulfur atom in the unsaturatedaliphatic heterocyclyl group is two, and the position of the heteroatomsand the double bonds in the ring is not limited as long as it ischemically stable. The unsaturated aliphatic heterocyclyl grouppreferably includes 5- to 10-membered unsaturated aliphatic heterocyclylgroup which may be mono- or bi-cyclic group, for example, 2-pyrrolinylgroup, 2-imidazolinyl group, and tetrahydroisoquinolyl group. Theunsaturated aliphatic heterocyclyl group more preferably includesmono-cyclic 5- to 6-membered unsaturated aliphatic heterocyclyl group,for example, 2-pyrrolinyl group, and 2-imidazolinyl group.

The “aryl group” used herein means mono-, bi-, or tri-cyclic aromatichydrocarbon group having 6-14 carbon atoms. The aryl group preferablyincludes 6- to 10-membered aryl group which may be mono- or bi-cyclicgroup, for example, phenyl group, 1-naphthyl group, and 2-naphthylgroup.

The aryl moiety in “aryloxy group”, “arylcarbonyl group”, “arylsulfonylgroup”, and the like used herein is as defined in the above “arylgroup”.

The “heteroaryl group” used herein means mono-, bi-, or tri-cyclicaromatic heterocyclyl group having 1 to 4 heteroatoms selectedindependently from the group consisting of nitrogen atom, oxygen atom,and sulfur atom and 1-14 carbon atoms. Each maximum number of oxygenatom and sulfur atom in the heteroaryl group is two, and the position ofthe heteroatoms in the ring is not limited as long as it is chemicallystable. The heteroaryl group preferably includes 5- to 10-memberedheteroaryl group which includes mono-cyclic 5- to 7-membered heteroarylgroup and bi-cyclic 8- to 10-membered heteroaryl group, for example,furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolylgroup, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolylgroup, furazanyl group, oxadiazolyl group, triazolyl group, pyridylgroup, pyrimidinyl group, pyrazinyl group, indolyl group, quinolylgroup, isoquinolyl group, quinazolinyl group, andimidazo[2,1-b][1,3]thiazolyl group.

The heteroaryl moiety in “heteroaryloxy group”, “heteroarylcarbonylgroup”, “heteroarylsulfonyl group”, and the like used herein is asdefined in the above “heteroaryl group”.

The substituent of “optionally-substituted alkyl group”,“optionally-substituted alkenyl group”, and “optionally-substitutedalkynyl group” in the present invention includes one or more selectedindependently from the following substituents of (ai)-(avi):

(ai) halogen atom, hydroxy group, carboxyl group, cyano group,

(aii) optionally-substituted amino group, optionally-substitutedcarbamoyl group, optionally-substituted sulfamoyl group,

(aiii) optionally-substituted alkoxy group,

wherein the substituent (s) of the optionally-substituted alkoxy groupis one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, amino groupwhich may be substituted with one or two the same or different alkyl,carbamoyl group which may be substituted with one or two the same ordifferent alkyl, haloalkoxy group, alkoxycarbonyl group,optionally-substituted alkoxy group, optionally-substituted aryl group,and optionally-substituted heteroaryl group, wherein the substituent (s)of the optionally-substituted alkoxy group may be HO—(CH₂CH₂O)_(n)—(wherein n is 1-5), HOOC—(CH₂CH₂O)_(n)— (wherein n is 1-5),R^(a)R^(b)N—(CH₂CH₂O)_(n)— (wherein n is 1-5),R^(a)R^(b)NOC—(CH₂CH₂O)_(n)— (wherein n is 1-5), R^(c)—(CH₂CH₂O)_(n)—(wherein n is 1-5), or R^(c)CO—(CH₂CH₂O)_(n)— (wherein n is 1-5),wherein R^(a) and R^(b) are independently hydrogen atom or C₁₋₃ alkylgroup, and R^(c) is amino acid group (which binds to C(O) at its Nterminus) or peptide (which binds to C(O) at its N terminus), whereinthe substituent of the optionally-substituted aryl group and theoptionally-substituted heteroaryl group is independently one or moresubstituents selected independently from the group consisting of halogenatom, hydroxy group, carboxyl group, alkyl group, haloalkyl group,alkoxy group, haloalkoxy group, alkoxycarbonyl group, nitro group, cyanogroup, and carbamoyl group,

(aiv) optionally-substituted alkylcarbonyl group, optionally-substitutedalkylcarbonyloxy group, optionally-substituted alkoxycarbonyl group,optionally-substituted alkylthio group, optionally-substitutedalkylsulfonyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, aminogroup which may be substituted with one or two the same or differentalkyl, carbamoyl group which may be substituted with one or two the sameor different alkyl, alkoxy group, haloalkoxy group, alkoxycarbonylgroup, optionally-substituted aryl group, and optionally-substitutedheteroaryl group, and wherein the substituent (s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup,

(av) optionally-substituted cycloalkyl group, optionally-substitutedcycloalkenyl group, optionally-substituted saturated aliphaticheterocyclyl group, optionally-substituted unsaturated aliphaticheterocyclyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, oxogroup, thioxo group, amino group which may be substituted with one ortwo the same or different alkyl, carbamoyl group which may besubstituted with one or two the same or different alkyl, alkoxy group,haloalkoxy group, optionally-substituted alkoxycarbonyl group,optionally-substituted alkylcarbonyl group, optionally-substitutedalkylsulfonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substitutedalkoxycarbonyl group, the optionally-substituted alkylcarbonyl group,the optionally-substituted alkylsulfonyl group, and theoptionally-substituted alkyl group is independently one or moresubstituents selected independently from the group consisting of halogenatom, hydroxy group, carboxyl group, alkoxy group, haloalkoxy group, andcarbamoyl group, and wherein the substituent(s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup, and

(avi) optionally-substituted aryl group, optionally-substitutedheteroaryl group, optionally-substituted aryloxy group,optionally-substituted heteroaryloxy group, optionally-substitutedarylcarbonyl group, optionally-substituted heteroarylcarbonyl group,optionally-substituted arylsulfonyl group, optionally-substitutedheteroarylsulfonyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group,optionally-substituted amino group, optionally-substituted carbamoylgroup, optionally-substituted sulfamoyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent (s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,haloalkoxy group, amino group which may be substituted with one or twothe same or different alkyl, carbamoyl group which may be substitutedwith one or two the same or different alkyl, amino acid group (whichbinds to the alkyl group at its N terminus), peptide (which binds to thealkyl group at its N terminus), and R^(d)C(O)— wherein R^(d) is aminoacid group or peptide (which binds to the carbonyl group at its Nterminus), and wherein the substituent (s) of the optionally-substitutedaryl group and the optionally-substituted heteroaryl group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, alkylgroup, haloalkyl group, alkoxy group, haloalkoxy group, alkoxycarbonylgroup, nitro group, cyano group, and carbamoyl group.

The substituent of “optionally-substituted cycloalkyl group”,“optionally-substituted cycloalkenyl group”, “optionally-substitutedsaturated aliphatic heterocyclyl group”, and “optionally-substitutedunsaturated aliphatic heterocyclyl group” in the present inventionincludes one or more selected independently from the followingsubstituents of (bi)-(bv):

(bi) halogen atom, hydroxy group, carboxyl group, cyano group, oxogroup, thioxo group, amidino group optionally-substituted with one ortwo the same or different alkoxycarbonyl group,

(bii) optionally-substituted amino group, optionally-substitutedcarbamoyl group, optionally-substituted sulfamoyl group,

(biii) optionally-substituted alkyl group, optionally-substituted alkoxygroup, optionally-substituted alkylcarbonyl group,optionally-substituted alkylcarbonyloxy group, optionally-substitutedalkoxycarbonyl group, optionally-substituted alkylthio group,optionally-substituted alkylsulfonyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group,carbamoyl group which may be substituted with one or two the same ordifferent alkyl, alkoxy group which may be substituted with alkoxy groupand/or carbamoyl group, haloalkoxy group, alkylthio group,alkoxycarbonyl group, optionally-substituted aryloxy group,optionally-substituted heteroaryloxy group, optionally-substituted arylgroup, optionally-substituted heteroaryl group, andoptionally-substituted amino group, wherein the substituent(s) of theoptionally-substituted aryloxy group, the optionally-substitutedheteroaryloxy group, the optionally-substituted aryl group, and theoptionally-substituted heteroaryl group is independently one or moresubstituents selected independently from the group consisting of halogenatom, hydroxy group, carboxyl group, alkyl group, haloalkyl group,alkoxy group, haloalkoxy group, alkoxycarbonyl group, nitro group, cyanogroup, and carbamoyl group, and wherein the substituent(s) of theoptionally-substituted amino group is one or two substituents selectedindependently from the group consisting of optionally-substituted alkylgroup, optionally-substituted alkylcarbonyl group,optionally-substituted alkylsulfonyl group, and carbamoyl group whichmay be substituted with one or two the same or differentoptionally-substituted alkyl group, wherein the substituent (s) of theoptionally-substituted alkyl group, the optionally-substitutedalkylcarbonyl group, the optionally-substituted alkylsulfonyl group, andthe optionally-substituted alkyl group in the carbamoyl group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, alkoxygroup, haloalkoxy group, and carbamoyl group, and

(biv) optionally-substituted cycloalkyl group, optionally-substitutedcycloalkenyl group, optionally-substituted saturated aliphaticheterocyclyl group, optionally-substituted unsaturated aliphaticheterocyclyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, oxogroup, thioxo group, amino group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent(s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup,

(bv) optionally-substituted aryl group, optionally-substitutedheteroaryl group, optionally-substituted aryloxy group,optionally-substituted heteroaryloxy group, optionally-substitutedarylcarbonyl group, optionally-substituted heteroarylcarbonyl group,optionally-substituted arylsulfonyl group, optionally-substitutedheteroarylsulfonyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, cyanogroup, optionally-substituted amino group, optionally-substitutedcarbamoyl group, optionally-substituted sulfamoyl group, alkoxy group,haloalkoxy group, alkoxycarbonyl group, optionally-substituted alkylgroup, optionally-substituted aryl group, and optionally-substitutedheteroaryl group, wherein the substituent (s) of theoptionally-substituted alkyl group is one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkoxy group, and haloalkoxy group, and wherein thesubstituent (s) of the optionally-substituted aryl group and theoptionally-substituted heteroaryl group is independently one or moresubstituents selected independently from the group consisting of halogenatom, hydroxy group, carboxyl group, alkyl group, haloalkyl group,alkoxy group, haloalkoxy group, alkoxycarbonyl group, nitro group, cyanogroup, and carbamoyl group.

The substituent of “optionally-substituted aryl group” and“optionally-substituted heteroaryl group” in the present inventionincludes one or more selected independently from the followingsubstituents of (ci) (cv):

(ci) halogen atom, hydroxy group, carboxyl group, cyano group, nitrogroup, methylenedioxy group, ethylenedioxy group,

(cii) optionally-substituted amino group, optionally-substitutedcarbamoyl group, optionally-substituted sulfamoyl group,

(ciii) optionally-substituted alkyl group, optionally-substitutedalkenyl group, optionally-substituted alkynyl group,optionally-substituted alkoxy group, optionally-substitutedalkylcarbonyl group, optionally-substituted alkylcarbonyloxy group,optionally-substituted alkoxycarbonyl group, optionally-substitutedalkylthio group, optionally-substituted alkylsulfonyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, aminogroup which may be substituted with one or two the same or differentalkyl, optionally-substituted alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted aryl group, andoptionally-substituted heteroaryl group, wherein the substituent(s) ofthe optionally-substituted alkoxy group, the optionally-substituted arylgroup, and the optionally-substituted heteroaryl group is independentlyone or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkyl group,haloalkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group,nitro group, cyano group, and carbamoyl group,

(civ) optionally-substituted cycloalkyl group, optionally-substitutedcycloalkenyl group, optionally-substituted saturated aliphaticheterocyclyl group, optionally-substituted unsaturated aliphaticheterocyclyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, oxogroup, thioxo group, amino group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent (s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent(s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup, and

(cv) optionally-substituted aryl group, optionally-substitutedheteroaryl group, optionally-substituted aryloxy group,optionally-substituted heteroaryloxy group, optionally-substitutedarylcarbonyl group, optionally-substituted heteroarylcarbonyl group,optionally-substituted arylsulfonyl group, optionally-substitutedheteroarylsulfonyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group,optionally-substituted amino group, optionally-substituted carbamoylgroup, optionally-substituted sulfamoyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent (s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup.

The substituent of “optionally-substituted amino group” in the presentinvention includes one or two selected independently from the followingsubstituents of (di)-(diii):

(di) optionally-substituted alkyl group, optionally-substituted alkenylgroup, optionally-substituted alkynyl group, optionally-substitutedalkylcarbonyl group, optionally-substituted alkylsulfonyl group,optionally-substituted alkoxycarbonyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, aminogroup which may be substituted with one or two the same or differentalkyl, carbamoyl group, alkoxy group, haloalkoxy group, alkoxycarbonylgroup, saturated aliphatic heterocyclyl group, unsaturated aliphaticheterocyclyl group, optionally-substituted aryl group, andoptionally-substituted heteroaryl group, wherein the substituent(s) ofthe optionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup,

(dii) optionally-substituted cycloalkyl group, optionally-substitutedcycloalkenyl group, optionally-substituted saturated aliphaticheterocyclyl group, optionally-substituted unsaturated aliphaticheterocyclyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, oxogroup, thioxo group, amino group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent(s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup, and

(diii) optionally-substituted aryl group, optionally-substitutedheteroaryl group, optionally-substituted arylcarbonyl group,optionally-substituted heteroarylcarbonyl group, optionally-substitutedarylsulfonyl group, optionally-substituted heteroarylsulfonyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, aminogroup which may be substituted with one or two the same or differentalkyl, carbamoyl group which may be substituted with one or two the sameor different alkyl, sulfamoyl group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent (s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent (s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup.

The substituent of “optionally-substituted carbamoyl group” in thepresent invention includes one or two selected independently from thefollowing substituents of (ei)-(eiv):

(ei) optionally-substituted alkyl group, optionally-substitutedhaloalkyl group, optionally-substituted alkenyl group,optionally-substituted alkynyl group, optionally-substitutedalkylcarbonyl group, optionally-substituted alkylsulfonyl group,optionally-substituted alkoxycarbonyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, amino group which maybe substituted with one or two the same or different alkyl, carbamoylgroup, alkoxy group, haloalkoxy group, alkoxycarbonyl group, saturatedaliphatic heterocyclyl group, unsaturated aliphatic heterocyclyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substituted arylgroup and the optionally-substituted heteroaryl group is independentlyone or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkyl group,haloalkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group,nitro group, cyano group, and carbamoyl group,

(eii) optionally-substituted cycloalkyl group, optionally-substitutedcycloalkenyl group, optionally-substituted saturated aliphaticheterocyclyl group, optionally-substituted unsaturated aliphaticheterocyclyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, oxogroup, thioxo group, amino group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent (s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent(s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup,

(eiii) optionally-substituted aryl group, optionally-substitutedheteroaryl group, optionally-substituted arylcarbonyl group,optionally-substituted heteroarylcarbonyl group, optionally-substitutedarylsulfonyl group, optionally-substituted heteroarylsulfonyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, aminogroup which may be substituted with one or two the same or differentalkyl, carbamoyl group which may be substituted with one or two the sameor different alkyl, sulfamoyl group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent (s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent (s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup, and

(eiv) C(O)R^(e) wherein R^(e) is amino acid group or peptide (whichbinds to C(O) at its N terminus), including carbamoyl group.

The substituent of “optionally-substituted sulfamoyl group” in thepresent invention includes one or more selected independently from thefollowing substituents of (fi)-(fiii):

(fi) optionally-substituted alkyl group, optionally-substitutedhaloalkyl group, optionally-substituted alkenyl group,optionally-substituted alkynyl group, optionally-substitutedalkylcarbonyl group, optionally-substituted alkylsulfonyl group,optionally-substituted alkoxycarbonyl group,

wherein the substituent (s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, amino group which maybe substituted with one or two the same or different alkyl, carbamoylgroup, alkoxy group, haloalkoxy group, alkoxycarbonyl group, saturatedaliphatic heterocyclyl group, unsaturated aliphatic heterocyclyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substituted arylgroup and the optionally-substituted heteroaryl group is independentlyone or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkyl group,haloalkyl group, alkoxy group, haloalkoxy group, alkoxycarbonyl group,nitro group, cyano group, and carbamoyl group,

(fii) optionally-substituted cycloalkyl group, optionally-substitutedcycloalkenyl group, optionally-substituted saturated aliphaticheterocyclyl group, optionally-substituted unsaturated aliphaticheterocyclyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, oxogroup, thioxo group, amino group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent(s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent(s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup, and

(fiii) optionally-substituted aryl group, optionally-substitutedheteroaryl group, optionally-substituted arylcarbonyl group,optionally-substituted heteroarylcarbonyl group, optionally-substitutedarylsulfonyl group, optionally-substituted heteroarylsulfonyl group,

wherein the substituent(s) of each optionally-substituted group isindependently one or more substituents selected independently from thegroup consisting of halogen atom, hydroxy group, carboxyl group, aminogroup which may be substituted with one or two the same or differentalkyl, carbamoyl group which may be substituted with one or two the sameor different alkyl, sulfamoyl group which may be substituted with one ortwo the same or different alkyl, alkoxy group, haloalkoxy group,alkoxycarbonyl group, optionally-substituted alkyl group,optionally-substituted aryl group, and optionally-substituted heteroarylgroup, wherein the substituent (s) of the optionally-substituted alkylgroup is one or more substituents selected independently from the groupconsisting of halogen atom, hydroxy group, carboxyl group, alkoxy group,and haloalkoxy group, and wherein the substituent (s) of theoptionally-substituted aryl group and the optionally-substitutedheteroaryl group is independently one or more substituents selectedindependently from the group consisting of halogen atom, hydroxy group,carboxyl group, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup, alkoxycarbonyl group, nitro group, cyano group, and carbamoylgroup.

In addition, two substituents in “optionally-substituted amino group”,“optionally-substituted carbamoyl group”, or “optionally-substitutedsulfamoyl group” may be combined together with the nitrogen atom towhich they are attached to form a 5- to 10-membered saturated orunsaturated nitrogen-containing aliphatic heterocycle. Saidnitrogen-containing aliphatic heterocycle includes pyrrolidine,piperidine, azepane, azocane, piperazine, morpholine, thiomorpholine,and tetrahydroisoquinoline. And, said nitrogen-containing aliphaticheterocycle may be substituted with one or more substituents selectedindependently from the group consisting of halogen, hydroxy group,carboxyl group, optionally-substituted alkyl group, haloalkyl group,alkoxy group, and haloalkoxy group, wherein the substituent(s) of theoptionally-substituted alkyl group include halogen atom, hydroxy group,carboxyl group, alkoxy group, haloalkoxy group, and carbamoyl group.

The “amino acid group” used herein means an amino acid in which thehydrogen atom in its N terminus is desorbed and the nitrogen in itsdehydrogened N terminus is attached to a carbon atom of anothermolecule.

The “amino acid” used herein should be broadly construed, and may benatural or unnatural ones. The natural amino acid used herein includes,for example, the amino acids mentioned below, and the unnatural aminoacid used herein includes, for example, besides the amino acidsmentioned below, an amino acid whose main chain structure is differentfrom those of natural amino acids such as α,α-di-substituted amino acid(α-methylalanine and the like), N-alkyl-α-amino acid, D-amino acid,β-amino acid, and α-hydroxylic acid; an amino acid whose side chainstructure is different from those of natural amino acids such asnorleucine and homohistidine; and an amino acid which has an extramethylene at the side chain such as “homo” amino acid,homophenylalanine, and homohistidine.

The “peptide” used herein is a polymer composed of plural amino acids.The number of amino acids is not limited, but includes, for example,2-50, 2-30, 2-10, 2-5, and 2-3 amino acids. The formation of the polymermay be linear or branch chain form, or cyclic form. Each “amino acid”which composes the peptide may be natural or unnatural one, which shouldbe broadly construed.

The specific amino acid residues of natural or unnatural amino acids ofthe present invention are shown below, but the unnatural amino acids arenot limited thereto.

Ala or A: alanine residueArg or R: arginine residueAsn or N: asparagine residueAsp or D: aspartate residueCys or C: cysteine residueGin or Q: glutamine residueGlu or E: glutamate residueGly or G: glycine residueHis or H: histidine residueIle or I: isoleucine residueLeu or L: leucine residueLys or K: lysine residueMet or M: methionine residuePhe or F: phenylalanine residuePro or P: proline residueSer or S: serine residueThr or T: threonine residueTrp or W: triptophan residueTyr or Y: tyrosine residueVal or V: valine residueAbu: 2-aminobutyrate residue (also referred to as α-aminobutyrateresidue)Orn: ornithine residueCit: citrulline residue

In the present compounds of formula (1), preferred substituents areshown as follows.

Formula (1):

wherein R¹-L- is R¹—OC(O)— or R¹—NHC(O)—, which shows that the carbonylgroup of R¹—OC(O)— or R¹—NHC(O)— is attached to the benzene ring, andits oxygen atom or nitrogen atom is attached to R¹.

Wherein R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group.

Preferably, R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup is one or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent (s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or

the (ii) optionally-substituted C₁₋₆ alkyl group may be any one of thefollowing groups of formulae (4)-(6):

formula (4):

wherein m is 1, 2, 3, 4, or 5, R⁷ is C₁₋₃ alkoxy group, amino acid group(which binds to C(O) at its N terminus), and peptide consisting of 2-3amino acid residues (which binds to C(O) at its N terminus),

formula (5):

R⁸-L²-(CH₂CH₂O)_(q)CH₂CH₂

(5)

wherein q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ is hydroxygroup, C₁₋₃ alkoxy group, amino group which may be substituted with oneor two the same or different C₁₋₃ alkyl, amino acid group (which bindsto L² at its N terminus), or peptide consisting of 2-3 amino acidresidues (which binds to L² at its N terminus),

formula (6):

wherein L³ is —CH₂— or C(O), and R⁹ is hydroxy group, C₁₋₃ alkoxy group,amino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl, amino acid group (which binds to L³ at its Nterminus), or peptide consisting of 2-3 amino acid residues (which bindsto L³ at its N terminus),

the substituent(s) of the (iii) optionally-substituted C₂₋₆ alkenylgroup, and the (iv) optionally-substituted C₂₋₆ alkynyl group areindependently one or more substituents selected independently from thegroup consisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, hydroxy group, and carboxyl group), optionally-substituted4- to 6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and 5- to 10-memberedheteroaryl group,

the substituent(s) of the (v) optionally-substituted 3- to 8-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group.

In an embodiment, R¹ is hydrogen atom, optionally-substituted C₁₋₆ alkylgroup, or any one of substituents of formula (4)-(6).

In another embodiment, R¹ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₃ alkyl group,

(iii) optionally-substituted C₂₋₄ alkenyl group,

(iv) optionally-substituted C₂₋₄ alkynyl group,

(v) optionally-substituted 3- to 6-membered cycloalkyl group,

(vi) optionally-substituted 4- to 6-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 6-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 6-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group.

In the above-mentioned preferred R¹, the optionally-substituted alkylgroup includes, preferably, one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, carboxyl group, carbamoyl group (which may be substitutedwith one or two the same or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ andR⁶ are independently hydrogen atom, C₁₋₃ alkyl group, carboxylmethylgroup, 2-hydroxyethyl group, or 2-aminoethyl group),optionally-substituted 3- to 6-membered cycloalkyl group (wherein thesubstituent(s) of said optionally-substituted 3- to 6-memberedcycloalkyl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group (wherein the substituent(s) of saidoptionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup is one or more substituents selected independently from the groupconsisting of amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, andcarboxyl group), and optionally-substituted 5- to 10-membered heteroarylgroup (wherein the substituent(s) of said optionally-substituted 5- to10-membered heteroaryl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group).

The preferred optionally-substituted alkyl group includes, for example,hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group,cyclopropyl group, cyclobutyl group, carboxymethyl group,carbamoylmethyl group, N,N-di(carboxymethyl)aminoethyl group,N,N-di(hydroxyethyl)aminoethyl group, 4-carboxycyclohexylmethyl group,4-hydroxycyclohexylmethyl group, 4-aminocyclohexylmethyl group,1,4-dimethylpiperazin-2-ylmethyl group,(1-methyl-1H-imidazol-2-yl)methyl group, 2-hydroxyethyl group,2-aminoethyl group, 2-carboxyethyl group, 2-methoxyethyl group,2-ethoxyethyl group, 2,2-dimethyl-2-hydroxyethyl group, 3-hydroxypropylgroup, 3-aminopropyl group, 3-carboxyethyl group, 3-methoxypropyl group,3-ethoxypropyl group, 2,3-dihydroxypropyl group,3-amino-3-carboxylpropyl group, tetrahydropyranyl group, tetrahydrofurylgroup, piperidinyl group, pyrrolidinyl group, and3-hydroxypyrrolidin-1-ylethyl group, more preferably, hydrogen atom,methyl group, ethyl group, propyl group, isopropyl group, cyclopropylgroup, cyclobutyl group, carboxymethyl group, carbamoylmethyl group,N,N-di(carboxymethyl)aminoethyl group, 4-aminocyclohexylmethyl group,1,4-dimethylpiperazin-2-ylmethyl group,(1-methyl-1H-imidazol-2-yl)methyl group, 2,3-dihydroxypropyl group,3-amino-3-carboxylpropyl group, 3-hydroxypyrrolidin-1-ylethyl group, and1,3-dicarboxylpropan-2-yl group.

In the above-mentioned preferred R¹, a preferred embodiment of theoptionally-substituted alkyl group is any one group of formula (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group or amino acid group (which binds to L² at its N terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus).

Even more preferably, it is any one group of formula (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group such as glutamic acid andarginine,

in formula (5), q is 1, L² is C(O), R⁸ is hydroxy group, or amino acidgroup such as glutamic acid and arginine,

in formula (6), L³ is C(O), R⁹ is amino acid group such as glutamic acidand arginine.

In another embodiment, R¹ is hydrogen atom.

R² is hydrogen atom, hydroxy group, or carboxyl group, preferablyhydrogen atom.

Ring A is a group of formula (2) or formula (3):

R³ in Ring A is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup, the (iii) optionally-substituted C₂₋₆ alkenyl group, the (iv)optionally-substituted C₂₋₆ alkynyl group, the (v)optionally-substituted 3- to 8-membered cycloalkyl group, the (vi)optionally-substituted 4- to 8-membered cycloalkenyl group, the (vii)optionally-substituted 4- to 8-membered saturated aliphatic heterocyclylgroup, the (viii) optionally-substituted 5- to 10-membered unsaturatedaliphatic heterocyclyl group, the (ix) optionally-substituted 6- to10-membered aryl group, and the (x) optionally-substituted 5- to10-membered heteroaryl group are independently one or more substituentsselected independently from the group consisting of hydroxy group,methoxy group, ethoxy group, carboxyl group, carbamoyl group which maybe substituted with one or two the same or different C₁₋₃ alkyl, andamino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl.

More preferably, R³ is hydrogen atom, C₁₋₃ alkyl group, or 3- to6-membered cycloalkyl group, even more preferably hydrogen atom ormethyl group.

R³ includes, for example, hydrogen atom, methyl group, ethyl group,propyl group (1-propyl group), isopropyl group (2-propyl group),cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexylgroup, preferably hydrogen atom or methyl group.

X in Ring A is nitrogen atom, NR⁴, or oxygen atom, provided that X isnot oxygen atom in the case of formula (2),

R⁴ in NR⁴ is

(i) hydrogen atom,

(ii) optionally-substituted C₁₋₆ alkyl group,

(iii) optionally-substituted C₂₋₆ alkenyl group,

(iv) optionally-substituted C₂₋₆ alkynyl group,

(v) optionally-substituted 3- to 8-membered cycloalkyl group,

(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,

(vii) optionally-substituted 4- to 8-membered saturated aliphaticheterocyclyl group,

(viii) optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group,

(ix) optionally-substituted 6- to 10-membered aryl group, or

(x) optionally-substituted 5- to 10-membered heteroaryl group,

wherein the substituent(s) of the (ii) optionally-substituted C₁₋₆ alkylgroup, the (iii) optionally-substituted C₂₋₆ alkenyl group, the (iv)optionally-substituted C₂₋₆ alkynyl group, the (v)optionally-substituted 3- to 8-membered cycloalkyl group, the (vi)optionally-substituted 4- to 8-membered cycloalkenyl group, the (vii)optionally-substituted 4- to 8-membered saturated aliphatic heterocyclylgroup, the (viii) optionally-substituted 5- to 10-membered unsaturatedaliphatic heterocyclyl group, the (ix) optionally-substituted 6- to10-membered aryl group, and the (x) optionally-substituted 5- to10-membered heteroaryl group are independently one or more substituentsselected independently from the group consisting of hydroxy group,methoxy group, ethoxy group, carboxyl group, carbamoyl group which maybe substituted with one or two the same or different C₁₋₃ alkyl, andamino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl.

Preferably, R⁴ in NR⁴ is hydrogen atom, C₁₋₃ alkyl group, or 3- to6-membered cycloalkyl group, and more preferably R⁴ is methyl group.

X includes, for example, nitrogen atom, NR⁴, and oxygen atom, providedthat X is not oxygen atom in the case of formula (2), and R⁴ includeshydrogen atom, methyl group, ethyl group, propyl group, isopropyl group,cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, tetrahydropyranyl group, tetrahydrofuryl group, piperidinylgroup, and pyrrolidinyl group. Preferably, X is nitrogen atom, NR⁴, oroxygen atom, provided that X is not oxygen atom in the case that Ring Ais the group of formula (2), and R⁴ is hydrogen atom, methyl group,ethyl group, propyl group, isopropyl group, or cyclopropyl group. Morepreferably, X is nitrogen atom, NCH₃ or oxygen atom, provided that X isnot oxygen atom in the case that Ring A is the group of formula (2).

Y in Ring A is carbon atom or CH.

Z in Ring A is carbon atom, CH, or nitrogen atom.

The combination of X, Y, and Z should be any one of chemically-possibleselections, which is X═Y—Z, X—Y═Z, or X—Y—Z.

When Ring A is the group of formula (2), the part of X

Y

Z is N═C—CH, N═C—N, NR⁴—C═C, NR⁴—CH—N, or NR⁴—CH—CH, preferably N═C—N orNR⁴—C═C. Specifically, it is N═C—CH, N═C—N, NCH₃—C═C, NCH₃—CH—N, orNCH₃—CH—CH, preferably N═C—N or NCH₃—C═C.

When Ring A is the group of formula formula (3), the part of X

Y

Z is N═C—CH, N═C—N, NR⁴—C═C, NR⁴—CH—N, NR⁴—CH—CH, O—C═C, O—CH—N, orO—CH—CH, preferably NR⁴—C═C or O—C═C. Specifically, it is N═C—CH, N═C—N,NCH₃—C═C, NCH₃—CH—N, NCH₃—CH—CH, O—C═C, O—CH—N, or O—CH—CH, preferablyNCH₃—C═C or O—C═C.

In the present compounds of formula (1), the most preferred combinationof substituents are shown as follows.

In formula (1),

R¹ is hydrogen atom, or the group of formula (6),

in formula (6), L³ is C(O), R⁹ is amino acid group (which binds to L³ atits N terminus),

R² is hydrogen atom,

Ring A is the group of formula (2) or formula (3),

when Ring A is the group of formula (2), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is N═C—N or NCH₃—C═C,

when Ring A is the group of formula (3), R³ is hydrogen atom or methylgroup, the part of X

Y

Z is NCH₃—C═C or O—C═C.

The present compound of formula (1) includes, preferably the followingcompound of formula (7).

Wherein Ring B is a group of formula (8), (9), or (10),

R¹ is

(i) hydrogen atom,

(ii) C₁₋₃ alkyl group

-   -   which may be substituted with one or more substituents selected        independently from the group consisting of hydroxy group,        methoxy group, ethoxy group, carboxyl group, carbamoyl group        (which may be substituted with one or two the same or different        C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ are independently hydrogen        atom, C₁₋₃ alkyl group, carboxylmethyl group, 2-hydroxyethyl        group, or 2-aminoethyl group), 3- to 6-membered cycloalkyl group        (which may be substituted with one or more substituents selected        independently from the group consisting of amino group which may        be substituted with one or two the same or different C₁₋₃ alkyl,        C₁₋₃ alkyl group, hydroxy group, and carboxyl group), 4- to        6-membered saturated aliphatic heterocyclyl group (which may be        substituted with one or more substituents selected independently        from the group consisting of amino group which may be        substituted with one or two the same or different C₁₋₃ alkyl,        C₁₋₃ alkyl group, hydroxy group, and carboxyl group), and 5- to        10-membered heteroaryl group (which may be substituted with one        or more substituents selected independently from the group        consisting of amino group which may be substituted with one or        two the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy        group, and carboxyl group),

(iii) the group of formula (4):

wherein m is 1, 2, 3, 4, or 5, R⁷ is C₁₋₃ alkoxy group, amino acid group(which binds to C(O) at its N terminus), and peptide consisting of 2-3amino acid residues (which binds to C(O) at its N terminus),

(iv) the group of formula (5):

R⁸-L²-(CH₂CH₂O)_(q)CH₂CH₂

  (5)

wherein q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ is hydroxygroup, C₁₋₃ alkoxy group, amino group which may be substituted with oneor two the same or different C₁₋₃ alkyl, amino acid group (which bindsto L² at its N terminus), or peptide consisting of 2-3 amino acidresidues (which binds to L² at its N terminus), or

(v) the group of formula (6):

wherein L³ is CH₂ or C(O), and R⁹ is hydroxy group, C₁₋₃ alkoxy group,amino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl, amino acid group (which binds to L³ at its Nterminus), or peptide consisting of 2-3 amino acid residues (which bindsto L³ at its N terminus);

X¹ is O or NR¹⁴; and

R¹³ and R¹⁴ are independently hydrogen atom, C₁₋₃ alkyl group, or 3- to6-membered cycloalkyl group.

Preferably, R¹ is any one group of formula (4)-(6),

in formula (4), m is 1, R⁷ is amino acid group (which binds to C(O) atits N terminus),

in formula (5), q is 1 or 2, L² is single bond or C(O), R⁸ is hydroxygroup, C₁₋₃ alkoxy group, or amino acid group (which binds to L² at itsN terminus),

in formula (6), L³ is C(O), R⁹ is hydroxy group or amino acid group(which binds to L³ at its N terminus).

More preferably, R¹ is a group of formula (6), L³ is C(O), R⁹ isL-glutamic acid.

In another embodiment, more preferably R¹ is a group of formula (4), mis 1, R⁷ is L-glutamic acid.

In another embodiment, R¹ is hydrogen atom.

Preferably, Ring B is the group of formula (8).

More preferably, R¹³ is hydrogen atom.

More preferably, R¹⁴ is methyl group.

The “pharmaceutically acceptable salt of the compound of formula (1)” inthe present invention includes a salt of the present compound having anacidic functional group (such as carboxyl group and phenolic hydroxygroup) and a base, and a salt of the present compound having a basicfunctional group (such as amino group and guanidyl) and an acid. Thesalt of the present compound having an acidic functional group and abase includes, for example, inorganic salts such as sodium salt,potassium salt, calcium salt, magnesium salt, aluminium salt, andammonium salt; organic salts such as triethylammonium salt,triethanolammonium salt, pyridinium salt, and diisopropylammonium salt;and basic amino acid salt such as arginine salt and lysine salt. Thesalt of the present compound having a basic functional group and an acidincludes, for example, hydrochloride, hydrobromide, sulfate, nitrate,acetate, trifluoroacetate, methanesulfonate, toluenesulfonate, andcitrate. These salts can be prepared by reacting the compound of formula(1) with a base or an acid in an appropriate solvent such as water,methanol, ethanol, acetone, ethyl acetate, chloroform, and ether. Theproduct after mixing with a base or an acid may be purified in aconventional method such as recrystallization.

In order to obtain the present compound as a salt, when the product isobtained in a salt form, it can be just purified without any process, orwhen the product is a free form, it can be obtained by a conventionalsalt-formation method, i.e., dissolving/suspending the product in anappropriate solvent and then adding an acid or a base thereto.

The compound of formula (1) and a pharmaceutically acceptable saltthereof can be in a solvate with water or various solvents, which isencompassed in the present invention.

The present invention encompasses the compound of formula (1) or apharmaceutically acceptable salt thereof. In addition, the presentinvention encompasses a hydrate thereof and a solvate thereof such asethanolate thereof. Furthermore, the present invention encompasses alltautomers, stereoisomers, and crystal forms thereof.

The compound of the present invention also includes an optical isomerwhich is based on chiral center, an atropisomer which is based onaxiality caused by intramolecular rotational hindrance orplanar-chirality, other stereoisomers, tautomer, and geometric isomer,all possible isomers of which and a mixture thereof are encompassed inthe present invention.

In particular, optical isomers and atropisomers can be obtained asracemate, or as optically active substance when using optically activestarting material or intermediate. If necessary, racemates of thecorresponding material or intermediate, or the final product can bephysically or optically divided to optically active enantiomers at anappropriate step in the process mentioned below in a known separatingmethod such as optically active column chromatography and fractionalcrystallization. For example, by diastereomer method, racemates can betransformed to two diastereomers by using an optically-active resolvingagent, and then the two diastereomers can be separated by a known methodsuch as fractional crystallization because such different diastereomersgenerally have different physical characters.

As one of the compound-groups of formula (1), the present compound offormula (1A) can be prepared from compounds of formula (1a) and formula(1b), for example, according to Scheme 1 shown below.

Wherein R¹¹, R¹², R¹⁵, and R¹⁶ are independently a protecting group ofhydroxy group; R¹³ is a protecting group of carboxyl group; R¹⁴ is afunctional group such as tributyltin group, pinacolboryl group, andhydroxyboryl group; R¹⁷ is hydrogen atom, a protected hydroxy group, ora protected carboxyl group; R¹⁸ is a halogen atom such as iodine andbromine; R², R³, X

Y

Z, X, Y, and Z are as defined in Term 1.

That is, the compound of formula (1a) and the compound of formula (1b)can be coupled at 20° C.-200° C. in a solvent (such as propionitrile,acetonitrile, tetrahydrofuran, 1,4-dioxane, and water, or a combinedsolvent thereof), in the presence of a base (such as potassiumcarbonate, triethylamine, and diisopropylethylamine), a phosphine ligand(such as 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), a coppercatalyst (such as copper (I) iodide), and a palladium catalyst (such astetrakis(triphenylphosphine)palladium andtris(dibenzylideneacetone)dipalladium) to prepare a compound of formula(1c). The compound of formula (1A) which is one of the compound-groupsof formula (1) can be prepared by suitably deprotecting the protectinggroups from the compound of formula (1c) in manner well-known by askilled person.

In the compounds of formulae (1a) and (1b), each protection groups ofR¹¹, R¹², R¹³, R¹⁵, and R¹⁶, and a protecting group in R¹⁷ are notlimited as long as they are protecting groups for hydroxy group orcarboxyl group, which are not cleaved during the above couplingreaction. It is possible to suitably use protecting groups well-known bya skilled person, which are described in Protective Group in OrganicSynthesis, 3rd edition (edited by Theodora W. Green, Peter G. M. Wuts,issued by John Wiley & Sons Inc, in 1999). For example, the protectinggroup for carboxyl group includes ester-type groups such as methylgroup, ethyl group, trimethylsilylethyl group and tert-butyl group, andthe protecting group for hydroxy group includes methyl group, pivaloylgroup, and methoxymethyl group.

As one of the compound-groups of formula (1), the present compound offormula (1B) can be prepared from a compound of formula (1A), forexample, according to Scheme 2 shown below.

Wherein R¹, R², R³, X

Y

Z, X, Y, Z, and L are as defined in Term 1.

That is, the compound of formula (1A) which is one of thecompound-groups of formula (1) can be reacted at 20° C.-120° C. in aninert solvent (such as toluene, dichloromethane, and chloroform), in thepresence of a halogenating agent (such as1-chloro-N,N,2-trimethylpropenylamine, phosphorus oxychloride,phosphorus trichloride, thionyl chloride, and phosphorus pentachloride),and then reacted with an alcohol compound or an amine compound whichcorresponds to a desired R¹ (such as propargyl alcohol andpropargylamine) at 0° C.-50° C. in an inert solvent (such asdichloromethane and chloroform) to give a compound of formula (1B) whichis one of the compound-groups of formula (1).

As one of the compound-groups of formula (1B), the present compound offormula (1Ba) can be prepared from compound (1c), for example, accordingto Scheme 3 shown below.

Wherein R⁰ is R¹ or a protected R¹; LG is a leaving group such ashalogen atom, alkylsulfonyloxy group, and arylsulfonyloxy group; R¹¹,R¹², R¹³, R¹⁵, R¹⁶ and R¹⁷ are as defined in Scheme 1; R¹, R², R³, X

Y

Z, X, Y, and Z are as defined in Term 1.

That is, among the protecting groups in the compound of formula (1c),R¹³ can be suitably de-protected in manner well-known by a skilledperson to give a compound of formula (1d). Compound (1d) can be reactedwith R⁰-LG at 0° C.-50° C. in an inert solvent in the presence of a baseas necessary to give compound (1e). The base used herein is not limitedas long as it is used in a normal reaction, which includes, for example,an organic base such as N-methylmorpholine, triethylamine,diisopropylethylamine, tributylamine, and pyridine; and an inorganicbase such as sodium hydrogencarbonate, potassium hydrogen carbonate,sodium carbonate, and potassium carbonate. The inert solvent used hereinincludes, for example, ether type solvents such as tetrahydrofuran,1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbon solventssuch as dichloromethane, chloroform, and dichloroethane; ketone solventssuch as acetone; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide,and a mixture thereof. The compound of formula (1Ba) which is one of thecompound-groups of formula (1B) can be prepared by suitably deprotectingthe protecting groups from the compound of formula (1e) in mannerwell-known by a skilled person.

In the compound of formula (1c), each protecting groups of R¹¹, R¹²,R¹⁵, and R¹⁶, and a protecting group in R¹⁷ are not limited as long asthey are not cleaved under the above deprotection condition of R¹³. Itis possible to suitably use protecting groups well-known by a skilledperson, which are described in Protective Group in Organic Synthesis,3rd edition (edited by Theodora W. Green, Peter G. M. Wuts, issued byJohn Wiley & Sons Inc, in 1999).

The compound of formula (1h) which is in the scope of theabove-mentioned compound of R⁰-LG can be prepared from compound offormula (1f), for example, according to Scheme 4 shown below.

Wherein R¹⁹ is a protected R⁹, LG is as defined in Scheme 3, R⁹ and L³are as defined in Term 2.

That is, the compound of formula (1f) can be reacted with propargylalcohol at 0° C.-50° C. in a solvent (such as dimethylsulfoxide,N,N-dimethylformamide, 1,4-dioxane, tert-butyl alcohol, and water, or acombined solvent thereof), in the presence of a reducing agent (such assodium ascorbate), a ligand (such astris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine), and a coppercatalyst (such as copper sulfate and copper iodide) to give the compoundof formula (1g). For example, compound (1h) can be prepared by reactingthe compound of formula (1g) with methanesulfonyl chloride,p-toluenesulfonyl chloride, or the like at 0° C.-50° C. in the presenceof a base such as triethylamine, diisopropylethylamine, pyridine,dimethylaminopyridine, sodium carbonate, and potassium carbonate.

The compounds of formulae (1fa) and (1j) which are in the scope of theabove-mentioned compound (1f) can be prepared from bromoacetic acid, forexample, according to Scheme 5 shown below.

Wherein R⁹ is as defined in Term 2, R¹⁹ is as defined in Scheme 4.

That is, to bromoacetic acid in a solvent (such as dimethylsulfoxide andN,N-dimethylformamide) is added sodium azide, and then the mixture canbe reacted at 0° C.-50° C. to give the compound of formula (1i). To thecompound of formula (1i) in a solvent (such as dimethylsulfoxide andN,N-dimethylformamide) are added a condensing agent (such asN,N′-diisopropylcarbodiimide and N,N′-dicyclohexylcarbodiimide), and anamino acid or peptide (whose N terminus is unprotected and the otherfunctional groups are unprotected or protected), and then the reactionmixture can be reacted at 0° C.-50° C. to give the compound of formula(1fa). The compound of formula (1 j) can be prepared by suitablydeprotecting the protecting group from the compound of formula (1fa) inmanner well-known by a skilled person.

In the compound of formula (1fa), each protecting group is not limitedas long as it is not cleaved under the above reaction condition. It ispossible to suitably use protecting groups well-known by a skilledperson, which are described in Protective Group in Organic Synthesis,3rd edition (edited by Theodora W. Green, Peter G. M. Wuts, issued byJohn Wiley & Sons Inc, in 1999). For example, the protecting group forcarboxyl group includes ester-type groups such as methyl group, ethylgroup, and tert-butyl group, and the protecting group for guanidyl groupincludes 4-methoxy-2,3,6-trimethylbenzenesulfonyl group,2,2,5,7,8-pentamethylchromane-6-sulfonyl group, and2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group.

As one of the compound-groups of formula (1B), the present compound offormula (1Bb) can be prepared from compound (1d), for example, accordingto Scheme 6 shown below.

Wherein R⁰ is as defined in Scheme 3; R¹¹, R¹², R¹⁵, R¹⁶, and R¹⁷ are asdefined in Scheme 1; R¹, R², R³, X

Y

Z, X, Y, and Z are as defined in Term 1.

That is, the compound of formula (1d) can be reacted with R⁰NH₂ at 0°C.-50° C. in an inert solvent together with a condensing agent in thepresence of a base as necessary to give compound (1k).

The base used herein is not limited as long as it is used in a normalreaction, which includes, for example, an organic base such asN-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine,and pyridine; and an inorganic base such as sodium hydrogencarbonate,potassium hydrogen carbonate, sodium carbonate, and potassium carbonate.

The condensing agent used herein includes what are disclosed in the 4thSeries of Experimental Chemistry, Vol. 22 (Jikken Kagaku Kouza, editedby the Chemical Society of Japan, issued by MARUZEN). It includes, forexample, phosphates such as diethyl cyanophosphate anddiphenylphosphoryl azide; carbodiimides such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (WSC.HCl(also referred to as EDC)) and dicyclohexylcarbodiimide (DCC); acombination of a disulfide (such as 2,2′-dipyridyl disulfide) and aphosphine (such as triphenylphosphine); phosphine halides such asN,N′-bis (2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl); acombination of an azodicarboxylate diester (such as diethylazodicarboxylate) and a phosphine (such as triphenylphosphine);2-halo-1-(lower alkyl)pyridinium halides such as2-chloro-1-methylpyridinium iodide; 1,1′-carbonyl diimidazole (CDI);diphenylphosphoryl azide (DPPA); diethyl phosphoryl cyanide (DEPC);tetrafluoroborates such as2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) and 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate (CIB);phosphates such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate (PYBOP), and2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU).

The inert solvent used herein includes, for example, ether type solventssuch as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;halogenated hydrocarbon solvents such as dichloromethane, chloroform,and dichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide,and a mixture thereof.

In addition, the compound of formula (1d) is reacted with a halogenatingagent (such as 1-chloro-N,N,2-trimethylpropenylamine, phosphorusoxychloride, phosphorus trichloride, thionyl chloride, and phosphoruspentachloride) at 20° C.-120° C. to give an acid halide thereof, andthen the acid halide can be reacted with R⁰NE₂ at 0° C.-50° C. in aninert solvent in the presence of a base as necessary to prepare compound(1k).

The inert solvent used herein includes, for example, ether type solventssuch as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;halogenated hydrocarbon solvents such as dichloromethane, chloroform,and dichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide.The base used herein is not limited as long as it is used in a normalreaction, which includes, for example, an organic base such asN-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine,and pyridine; and an inorganic base such as sodium hydrogencarbonate,potassium hydrogen carbonate, sodium carbonate, and potassium carbonate.

The compound of formula (1Bb) which is one of the compound-groups offormula (1B) can be prepared by suitably deprotecting the protectinggroups from the compound of formula (1k) in manner well-known by askilled person.

As one of the compound-groups of formula (1B), the present compound offormula (1Bd) can be prepared from compound (1Bc), for example,according to Scheme 7 shown below.

Wherein R⁹ and L³ are as defined in Term 2; R¹⁹ is as defined in Scheme4; R², R³, X

Y

Z, X, Y, Z, and L are as defined in Term 1.

That is, the compound of formula (1Bc) which is one of thecompound-groups of formula (1B) is reacted with a compound of formula(1f) at 0° C.-50° C. in a solvent (such as dimethylsulfoxide,N,N-dimethylformamide, 1,4-dioxane, tert-butanol, and water, or acombined solvent thereof), in the presence of a reducing agent (such assodium ascorbate), a ligand (such astris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine), and a coppercatalyst (such as copper sulfate and copper iodide). The compound offormula (1Bd) can be prepared by suitably deprotecting the protectinggroups from the product in manner well-known by a skilled person. Inaddition, the compound of formula (1Bd) can be also obtained by usingthe compound of formula (1j) instead of the compound of formula (1f) inthe above reaction.

The above-mentioned compound (1a) can be prepared from a compound offormula (11), for example, according to Scheme 8 shown below.

Wherein R^(n), R¹², R¹³, and R¹⁴ are as defined in Scheme 1.

That is, the compound of formula (11) can be reacted with a tin reagentsuch as tributyltin chloride, and a Grignard reagent such asisopropylmagnesium chloride at −78° C. to 30° C. in a solvent (such astetrahydrofuran and 1,4-dioxane), or with a boronating reagent (such astrimethoxyborane), and a Grignard reagent (such as isopropylmagnesiumchloride-lithium chloride complex) at −78° C. to 30° C. in a solvent(such as tetrahydrofuran and 1,4-dioxane) to give the compound offormula (1a).

The compound of formula (11) is a known compound (for example, compoundsdisclosed in Angew. Chem. Int. Ed., 52, p 3421-3424 (2013), or ChemLett., 36, p 1382 (2007)), or can be prepared in manner well-known by askilled person. For example, the compounds described in the presentreference examples may be used.

As one of the compound-groups of compound (1b), the compound of formula(1ba) can be prepared from a compound of formula (1m), according toScheme 9 shown below.

Wherein R³ is as defined in Term 1, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are asdefined in Scheme 1.

That is, the compound of formula (1m) can be reacted with a reagentcorresponding to R³ (such as ethyl 3-oxopropanoate, ethyl acetoacetate,and ethyl 3-oxovalerate) at 0° C.-150° C. in a solvent such aspolyphosphoric acid to give a compound of formula (1n). The compound offormula (1n) can be reacted with

(Ai) a halogenating agent such as N-iodosuccinimide at 0° C.-100° C. ina solvent such as acetonitrile, tetrahydrofuran and 1,4-dioxane,

(Aii) sodium acetate or the like, and a halogenating agent such asbromine at 0° C.-100° C. in a solvent such as acetic acid, or

(Aiii) potassium iodide or the like, and a halogenating agent such asiodine at 0° C.-100° C. in an aqueous sodium hydroxide solution, to givethe compound of formula (1ba).

The compound of formula (1m) can be prepared, for example, in the mannerdisclosed in J. Med. Chem., 2015, 58(5), p 2195-2205, or is commerciallyavailable.

As one of the above-mentioned compound (1b), the compound of formula(1bb) can be prepared from a compound of formula (1o), for example,according to Scheme 10 shown below.

Wherein R³ and R⁴ are as defined in Term 1, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ areas defined in Scheme 1.

That is, the compound of formula (1o) is reacted with a base (such assodium methoxide) and a reagent corresponding to R³ (such as ethylformate and ethyl acetate) at 0° C.-50° C. in a solvent (such asdimethoxyethane, 1,4-dioxane and cyclopentylmethyl ether), and then thereaction mixture can be reacted at 0° C.-120° C. in 4 mol/L hydrochloricacid/a solvent (such as dioxane) to give the compound of formula (1p).The compound of formula (1p) can be reacted with

(Bi) a halogenating agent such as N-iodosuccinimide at 0° C.-100° C. ina solvent (such as acetonitrile, tetrahydrofuran and 1,4-dioxane),

(Bii) sodium acetate or the like, and a halogenating agent such asbromine at 0° C.-100° C. in a solvent (such as acetic acid), or

(Biii) potassium iodide or the like, and a halogenating agent such asiodine at 0° C.-100° C. in an aqueous sodium hydroxide solution,

to give a compound of formula (1q). The compound of formula (1q) can bereacted with a base (such as potassium carbonate and cesium carbonate),and an alkylating agent corresponding to R⁴ (such as methyl iodide,ethyl iodide, and propyl iodide) at 0° C.-100° C. in a solvent (such asN,N-dimethylformamide and dimethylsulfoxide) to give the compound offormula (1bb). It is unnecessary to transfer from formula (1q) toformula (1bb) when R⁴ is hydrogen atom.

The aniline compound of formula (1o) can be prepared, for example, inthe manner disclosed in Tetrahedron, Volume 63, Issue 2, p 474-491(2007), or is commercially available.

Besides the above-mentioned process, the quinolin-4(1H)-one compound offormula (1p) can be prepared, for example, in the manner disclosed inBioorg. Med. Chem. 13, p 1661-1671 (2005), or Tetrahedron Lett. 50, p6494-6497 (2009), or is commercially available.

As one of the compound-groups of formula (1), the present compound offormula (1C) can be prepared from compounds of formula (1a) and formula(1r), for example, according to Scheme 11 shown below.

Wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are as defined inScheme 1, R², R³, X

Y

Z, X, Y, and Z are as defined in Term 1.

That is, the compound of formula (1a) and the compound of formula (1r)can be coupled at 20° C.-200° C. in a solvent (such as propionitrile,acetonitrile, tetrahydrofuran, 1,4-dioxane, and water, or a combinedsolvent thereof), in the presence of a base (such as potassiumcarbonate, triethylamine and diisopropylethylamine), a phosphine ligand(such as 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), a coppercatalyst (such as copper (I) iodide), and a palladium catalyst (such astetrakis(triphenylphosphine)palladium andtris(dibenzylideneacetone)dipalladium) to prepare a compound of formula(1s). The compound of formula (1C) which is one of the compound-groupsof formula (1) can be prepared by suitably deprotecting the protectinggroups from the compound of formula (1s) in manner well-known by askilled person.

In the compounds of formula (1a) and formula (1r), each protectiongroups of R¹¹, R¹², R¹³, R¹⁵, and R¹⁶, and a protecting group in R¹⁷ arenot limited as long as they are protecting groups for hydroxy group orcarboxyl group, which are not cleaved during the above couplingreaction. It is possible to suitably use protecting groups well-known bya skilled person, which are described in Protective Group in OrganicSynthesis, 3rd edition (edited by Theodora W. Green, Peter G. M. Wuts,issued by John Wiley & Sons Inc, in 1999). For example, the protectinggroup for carboxyl group includes ester-type groups such as methylgroup, ethyl group, and tert-butyl group, and the protecting group forhydroxy group includes methyl group, pivaloyl group, and methoxymethylgroup.

As one of the compound-groups of formula (1), the present compound offormula (1D) can be prepared from compounds of formula (1C), forexample, according to Scheme 12 shown below.

Wherein R¹, R², R³, X

Y

Z, X, Y, Z, and L are as defined in Term 1.

That is, the compound of formula (1C) which is one of thecompound-groups of formula (1) can be reacted at 20° C.-120° C. in aninert solvent (such as toluene, dichloromethane, and chloroform), in thepresence of a halogenating agent (such as1-chloro-N,N,2-trimethylpropenylamine, phosphorus oxychloride,phosphorus trichloride, thionyl chloride, and phosphorus pentachloride),and then reacted with an alcohol compound or an amine compound whichcorresponds to a desired R¹ (such as propargyl alcohol andpropargylamine) at 0° C.-50° C. in an inert solvent (such asdichloromethane and chloroform) to give the compound of formula (1D)which is one of the compound-groups of formula (1).

As one of the compound-groups of formula (1D), the compound of formula(1Da) can be prepared from compound (1s), for example, according toScheme 13 shown below.

Wherein R¹¹, R¹², R¹³, R¹⁵, R¹⁶, and R¹⁷ are as defined in Scheme 1, R⁰and LG are as defined in Scheme 3, R¹, R², R³, X

Y

Z, X, Y, and Z is as defined in Term 1.

That is, among the protecting groups in the compound of formula (1s),R¹³ can be suitably de-protected in manner well-known by a skilledperson to give a compound of formula (1t). Compound (1t) can be reactedwith R⁰-LG at 0° C.-50° C. in an inert solvent in the presence of a baseas necessary to give compound (1u). The base used herein is not limitedas long as it is used in a normal reaction, which includes, for example,an organic base such as N-methylmorpholine, triethylamine,diisopropylethylamine, tributylamine, and pyridine; and an inorganicbase such as sodium hydrogencarbonate, potassium hydrogen carbonate,sodium carbonate, and potassium carbonate. The inert solvent used hereinincludes, for example, ether type solvents such as tetrahydrofuran,1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbon solventssuch as dichloromethane, chloroform, and dichloroethane; and aproticsolvents such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide,and hexamethylphosphoramide, and a mixture thereof. The compound offormula (1Da) which is one of the compound-groups of formula (1D) can beprepared by suitably deprotecting the protecting groups from thecompound of formula (1u) in manner well-known by a skilled person.

In the compound of formula (1s), each protection groups of R¹¹, R¹²,R¹⁵, and R¹⁶, and a protecting group in R¹⁷ are not limited as long asthey are not cleaved under the above deprotection condition of R¹³. Itis possible to suitably use protecting groups well-known by a skilledperson, which are described in Protective Group in Organic Synthesis,3rd edition (edited by Theodora W. Green, Peter G. M. Wuts, issued byJohn Wiley & Sons Inc, in 1999).

As one of the compound-groups of formula (1D), the compound of formula(1Db) can be prepared from compound (1t), for example, according toScheme 14 shown below.

Wherein R¹¹, R¹², R¹⁵, R¹⁶, and R¹⁷ are as defined in Scheme 1, R⁰ is asdefined in Scheme 3, R¹, R², R³, X

Y

Z, X, Y, and Z are as defined in Term 1.

That is, the compound of formula (1t) can be reacted with R⁰NH₂ at 0°C.-50° C. in an inert solvent together with a condensing agent in thepresence of a base as necessary to give compound (1v).

The base used herein is not limited as long as it is used in a normalreaction, which includes, for example, an organic base such asN-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine,and pyridine; and an inorganic base such as sodium hydrogencarbonate,potassium hydrogen carbonate, sodium carbonate, and potassium carbonate.

The condensing agent used herein includes what are disclosed in the 4thSeries of Experimental Chemistry, Vol. 22 (Jikken Kagaku Kouza, editedby the Chemical Society of Japan, issued by MARUZEN). It includes, forexample, phosphates such as diethyl cyanophosphate anddiphenylphosphoryl azide; carbodiimides such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (WSC.HCl(also referred to as EDC)) and dicyclohexylcarbodiimide (DCC); acombination of a disulfide (such as 2,2′-dipyridyl disulfide) and aphosphine (such as triphenylphosphine); phosphine halides such asN,N′-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl); a combinationof an azodicarboxylate diester (such as diethyl azodicarboxylate) and aphosphine (such as triphenylphosphine); 2-halo-1-(lower alkyl)pyridiniumhalides such as 2-chloro-1-methylpyridinium iodide; 1,1′-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); diethyl phosphorylcyanide (DEPC); tetrafluoroborates such as2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) and 2-chloro-1,3-dimethylimidazolidinium tetrafluoroborate (CIB);phosphates such as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate (PYBOP), and2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU).

The inert solvent used herein includes, for example, ether type solventssuch as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;halogenated hydrocarbon solvents such as dichloromethane, chloroform,and dichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide,and a mixture thereof.

In addition, the compound of formula (1t) is reacted with a halogenatingagent (such as 1-chloro-N,N,2-trimethylpropenylamine, phosphorusoxychloride, phosphorus trichloride, thionyl chloride, and phosphoruspentachloride) at 20° C.-120° C. to give an acid halide thereof, andthen the acid halide can be reacted with R⁰NH₂ at 0° C.-50° C. in aninert solvent in the presence of a base as necessary to prepare compound(1v).

The inert solvent used herein includes, for example, ether type solventssuch as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;halogenated hydrocarbon solvents such as dichloromethane, chloroform,and dichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoramide,and a mixture thereof. The base used herein is not limited as long as itis used in a normal reaction, which includes, for example, an organicbase such as N-methylmorpholine, triethylamine, diisopropylethylamine,tributylamine, and pyridine; and an inorganic base such as sodiumhydrogencarbonate, potassium hydrogen carbonate, sodium carbonate, andpotassium carbonate.

The compound of formula (1Db) which is one of the compound-groups offormula (1D) can be prepared by suitably deprotecting the protectinggroups from the compound of formula (1v) in manner well-known by askilled person.

As one of the compound-groups of formula (1D), the present compound offormula (1Dd) can be prepared from compound of formula (1Dc), forexample, according to Scheme 15 shown below.

Wherein R⁹ and L³ are as defined in Term 2, R¹⁹ is as defined in Scheme4, R², R³, X

Y

Z, X, Y, Z, and L are as defined in Term 1.

That is, the compound of formula (1Dc) which is one of thecompound-groups of formula (1D) is reacted with a compound of formula(1f) at 0° C.-50° C. in a solvent (such as dimethylsulfoxide,N,N-dimethylformamide, 1,4-dioxane, tert-butanol, and water, or acombined solvent thereof), in the presence of a reducing agent (such assodium ascorbate), a ligand (such astris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine), and a coppercatalyst (such as copper sulfate and copper iodide). The compound offormula (1Dd) can be prepared by suitably deprotecting the protectinggroups from the product in manner well-known by a skilled person. Inaddition, the compound of formula (1Dd) can be also obtained by usingthe compound of formula (1j) instead of the compound of formula (1f) inthe above reaction.

The compound of formula (1ra) which is in the scope of theabove-mentioned compound (1r) can be prepared from compound of formula(1w), for example, according to Scheme 16 shown below.

Wherein R³ and R⁴ is as defined in Term 1, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are asdefined in Scheme 1.

That is, the compound of formula (1w) is reacted with a reagentcorresponding to R³ (such as ethyl 3-oxopropanoate, ethyl acetoacetate,and ethyl 3-oxovalerate) at 100° C.-200° C. without a solvent or in asolvent (such as toluene and xylene), and then the reaction mixture canbe reacted at 0° C.-100° C. under acidic condition (such as underconcentrated sulfuric acid) to give a compound of formula (1x). Thecompound of formula (1x) can be reacted with

a halogenating agent such as N-iodosuccinimide and N-bromosuccinimide at0° C.-100° C. in a solvent such as acetonitrile, tetrahydrofuran,N,N-dimethylformamide, and 1,4-dioxane,

sodium acetate or the like, and a halogenating agent such as bromine at0° C.-100° C. in a solvent such as acetic acid, or

potassium iodide or the like, and a halogenating agent such as iodine at0° C.-100° C. in an aqueous sodium hydroxide solution,

to give the compound of formula (1y).

The compound of formula (1y) can be reacted with a base (such aspotassium carbonate and cesium carbonate), and an alkylating agentcorresponding to R⁴ (such as methyl iodide, ethyl iodide, and propyliodide) at 0° C.-100° C. in a solvent (such as N,N-dimethylformamide anddimethylsulfoxide) to give the compound of formula (1ra).

The aniline compound of formula (1w) can be prepared, for example, inthe manner disclosed in WO 2003/099762, or is commercially available.

The quinolin-2(1H)-one compound of formula (1x) can be prepared, forexample, in the manner disclosed in Heterocycles, 65, p 2095-2105(2005), or Org. Lett., 16, p 3568-3571 (2014), or is commerciallyavailable.

The compound of formula (1rb) which is in the scope of theabove-mentioned compound (1r) can be prepared from compound of formula(1z), for example, according to Scheme 17 shown below.

Wherein R³ is as defined in Term 1, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are asdefined in Scheme 1.

That is, the compound of formula (1z) can be reacted with a reagentcorresponding to R³ (such as ethyl 3-oxopropanoate, ethyl acetoacetate,and ethyl 3-oxovalerate) at 0° C.-100° C. under acidic condition (suchas concentrated sulfuric acid, methanesulfonic acid, andp-toluenesulfonic acid) to give a compound of formula (1aa). Inaddition, the 2H-chromen-2-one compound of formula (1aa) is commerciallyavailable. The compound of formula (1aa) can be reacted with

(i) a halogenating agent such as N-iodosuccinimide at 0° C.-100° C. in asolvent (such as acetonitrile, tetrahydrofuran and 1,4-dioxane),

(ii) sodium acetate or the like, and a halogenating agent such asbromine at 0° C.-100° C. in a solvent (such as acetic acid), or

(iii) potassium iodide or the like, and a halogenating agent such asiodine at 0° C.-100° C. in an aqueous sodium hydroxide solution,

to give a compound of formula (1rb).

The compound of formula (1z) can be prepared, for example, in the mannerdisclosed in WO 2005/000838, or is commercially available.

The compound of formula (1ac) which is in the scope of theabove-mentioned compound of R⁰-LG can be prepared from compound offormula (1ab), for example, according to Scheme 18 shown below.

Wherein R¹⁹ is as defined in Scheme 4, LG is as defined in Scheme 3, mis as defined in Term 2.

That is, compound (1ac) can be prepared by reacting a compound offormula (1ab) with an amino acid or peptide which is protected by usinga condensing agent at 0° C.-50° C., in the presence of a base asnecessary. The solvent used herein includes, for example, ether typesolvents such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane;halogenated hydrocarbon solvents such as dichloromethane, chloroform,and dichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, and dimethylsulfoxide. The base used hereinincludes, for example, triethylamine, diisopropylethylamine, pyridine,sodium hydrogencarbonate, potassium hydrogen carbonate, sodiumcarbonate, and potassium carbonate, which is not limited as long as itis used in a normal reaction. The condensing agent used herein includeswhat are disclosed in the 4th Series of Experimental Chemistry, Vol. 22(Jikken Kagaku Kouza, edited by the Chemical Society of Japan, issued byMARUZEN).

In addition, the compound of formula (1ab) is reacted with ahalogenating agent (such as 1-chloro-N,N,2-trimethylpropenylamine,phosphorus oxychloride, phosphorus trichloride, thionyl chloride, andphosphorus pentachloride) at 20° C.-120° C. to give an acid halidethereof, and then the acid halide can be reacted with a protected aminoacid or a protected peptide at 0° C.-50° C. in the presence of a base asnecessary to prepare compound (1ac). As the acid halide compound offormula (1ab), a commercially available one may be used. The solventused herein includes, for example, ether type solvents such astetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; halogenatedhydrocarbon solvents such as dichloromethane, chloroform, anddichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, and dimethylsulfoxide. The base used hereinincludes, for example, triethylamine, diisopropylethylamine, pyridine,sodium hydrogencarbonate, potassium hydrogen carbonate, sodiumcarbonate, and potassium carbonate, which is not limited as long as itis used in a normal reaction.

The carboxylic acid compound of formula (1ab) is commercially available.

The compound of formula (1ag) which is in the scope of theabove-mentioned R⁰-LG can be prepared from compound of formula (1ad),for example, according to Scheme 19 shown below.

Wherein R¹³ is as defined in Scheme 1, R¹⁹ is as defined in Scheme 4, LGis as defined in Scheme 3, q is as defined in Term 2.

That is, compound (1ae) can be prepared by reacting compound (1ad) withmethanesulfonyl chloride, p-toluenesulfonyl chloride, or the like at 0°C.-50° C. in the presence of a base such as triethylamine,diisopropylethylamine, pyridine, dimethylaminopyridine, sodiumcarbonate, and potassium carbonate. The compound of compound (1af) canbe prepared by suitably deprotecting the protecting group R¹³ from thecompound of compound (1ae) in manner well-known by a skilled person. Thecompound (1af) can be reacted with a protected amino acid or a protectedpeptide together with a condensing agent in a solvent (such astetrahydrofuran, dichloromethane, chloroform, acetonitrile,N,N-dimethylformamide, and dimethylsulfoxide), in the presence of a baseas necessary to prepare compound (1ag). The base used herein includes,for example, triethylamine, diisopropylethylamine, pyridine, sodiumhydrogencarbonate, potassium hydrogen carbonate, sodium carbonate, andpotassium carbonate, which is not limited as long as it is used in anormal reaction. The condensing agent used herein includes what aredisclosed in the 4th Series of Experimental Chemistry, Vol. 22 (JikkenKagaku Kouza, edited by the Chemical Society of Japan, issued byMARUZEN). In addition, the compound (1af) is reacted with a halogenatingagent (such as 1-chloro-N,N, 2-trimethylpropenylamine, phosphorusoxychloride, phosphorus trichloride, thionyl chloride, and phosphoruspentachloride) at 20° C.-120° C. to give an acid halide thereof, andthen the acid halide can be reacted with a protected amino acid or aprotected peptide at 0° C.-50° C. in a solvent (such as tetrahydrofuran,dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, anddimethylsulfoxide), in the presence of a base as necessary to preparecompound (1ag). The base used herein includes, for example,triethylamine, diisopropylethylamine, pyridine, sodiumhydrogencarbonate, potassium hydrogen carbonate, sodium carbonate, andpotassium carbonate, which is not limited as long as it is used in anormal reaction. In the above-mentioned process from compound (1ad) tocompound (1ag), it is possible to change the routes, i.e., firstpreparing compound (1ah), then transferring it to compound (1ai), andfinally obtaining compound (1ag), as each method is the same as above.

The above-mentioned compound (1ad) is commercially available or can beprepared from a compound of formula (1aj), for example, according toScheme 20 shown below.

Wherein R¹³ is as defined in Scheme 1, q is as defined in Term 2.

That is, compound (1ad) can be prepared by reacting compound (1aj) withcompound (1ak) at 0° C.-80° C. under a basic condition. The base usedherein includes, for example, metallic hydride such as sodium hydride,and metallic alkoxide such as potassium t-butoxide. The solvent usedherein includes, for example, ether type solvents such astetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; halogenatedhydrocarbon solvents such as dichloromethane, chloroform, anddichloroethane; and aprotic solvents such as acetonitrile,N,N-dimethylformamide, and dimethylsulfoxide.

The diol compound of formula (1aj) is commercially available.

In any processes of the present invention, if it is necessary to protecta specific functional group (such as hydroxy group and carboxyl group)in reactant reagents with a suitable protecting group, the functionalgroup may be protected/deprotected with one or more protecting groups inmanner well-known by a skilled person in a suitable step.

The compound of formula (1) or a pharmaceutically acceptable saltthereof exhibits the inhibitory activity of neuronaloutgrowth-inhibitory factor, i.e., semaphorin inhibitory activity,specifically, semaphorin 3A inhibitory activity, and hence it is usefulas a nerve regeneration promoter.

In addition, the compound of formula (1) or a pharmaceuticallyacceptable salt thereof is useful as a medicament for treating orpreventing neurodegenerative disease or neuropathy disorder whichincludes a disease associated with neurodegeneration or neuropathy(neurological disorder) such as spinal cord injury. The typicaldisorder/disease includes, for example, dysosmia, traumatic neurologicaldisorder, cerebral-infarct neurological disorder, facial palsy, diabeticneurosis, glaucoma, retinitis pigmentosa, dry eye, Alzheimer's disease,Parkinson's disease, neurodegenerative disease, muscular dysgeniclateral sclerosis, amyotrophic lateral sclerosis, Huntington's disease,cerebral infarct, and traumatic neurodegenerative disease.

The above-mentioned neuropathy disorder or neurodegenerative diseasewhich includes a disease associated with neurodegeneration orneurological disorder such as spinal cord injury includes, for example,neuropathy disorder including a disease associated with central nerveinjury, neuropathy disorder including a disease associated withperipheral nerve injury, and central neurodegenerative disease.

The neuropathy disorder including a disease associated with centralnerve injury includes, for example, neurological disorder caused byinjury such as spinal cord injury, neurological disorder caused bycerebral infarct or the like, and facial palsy.

The neuropathy disorder including a disease associated with peripheralnerve injury includes, for example, dysosmia caused by aging or thelike, facial palsy, diabetic neurosis, glaucoma, and dry eye. Thecentral neurodegenerative disease includes, for example, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, traumatic neurodegenerative disease, and musculardysgenic lateral sclerosis.

Furthermore, the compound of formula (1) or a pharmaceuticallyacceptable salt thereof is useful as a medicament for treating orpreventing a disease associated with angiogenesis that VEGF165 takes arole in, which have a common receptor, neuropilin.

The compound of formula (1) or a pharmaceutically acceptable saltthereof can promote the regeneration of olfactory nerve or sensory nervewhich is a peripheral nerve; and the regeneration of central nerve whichis located medial to cerebrospinal barrier, such as olfactory bulb,cerebral cortex, hippocampus, striatum, thalamus, diencephalon,midbrain, cerebellum, pons, medulla oblongata, spinal cord, and retinain brain or spinal cord.

The compound of formula (1) or a pharmaceutically acceptable saltthereof is useful as a medicament for treating or preventing aneurological disease associated with ischemic damage. The neurologicaldisease associated with ischemic damage (ischemic neuronal disease) usedherein includes retinal neurological disorder caused by ischemia, andischemic cerebrovascular disease. The retinal neurological disorder usedherein includes, for example, glaucoma, central retinal arteryocclusion, central branch retinal artery occlusion, central retinal veinocclusion, central branch retinal vein occlusion, ischemic opticneuropathy, diabetic retinopathy, macular degeneration, and retinopathyof prematurity, preferably diabetic retinopathy. And, the ischemiccerebrovascular disease used herein includes, for example, cerebralemboli, transient cerebral ischemia, subclavian steal syndrome,Wallenberg's syndrome (lateral medullary syndrome), cerebral thrombosis,lacunar infarct, reversible ischemic neurological deficit, cerebralinfarct, moyamoya disease (spontaneous occlusion of the circle ofWillis), cerebral hypoxia, sinus thrombosis, and postoperative spinalcord ischemia. The compound of the present invention has a protectiveeffect for retinal neuron, and it is useful for treating or preventingretinal neurological disorder caused by ischemia, especially.

In addition, the compound of formula (1) or a pharmaceuticallyacceptable salt thereof is useful as a medicament for treating orpreventing corneal disease. The corneal disease used herein includes,for example, dry eye, keratitis, leukoma, corneal infection, cornealdegeneration, corneal dystrophy, corneal stromal dystrophy, bullouskeratopathy, keratoconus, corneal endothelial decompensation, cornealulcer, nerve-paralytic keratopathy, diabetic keratopathy, chemicalocular injury, and corneal burn. Preferably, it includes dry eye,keratitis, bullous keratopathy, corneal ulcer, nerve-paralytickeratopathy, and diabetic keratopathy, more preferably dry eye.

The promoting activity of nerve regeneration in a nerve regenerationpromoter denotes a promoting effect of nerve regeneration in centralnerve and/or peripheral nerve, i.e., which means promoting activity fornerve regeneration in central tissue composed of brain, spinal cord, andthe like, and peripheral tissue that is various tissues of body surfaceand body inside located in marginal/peripheral sites which are otherthan central tissue. The nerve regeneration for nerve regeneration incentral nerve includes, not only nerve regeneration that the perikaryonlocated in central region such as retinal neuron and cerebral corticalneuron puts out axon to project to another nerve cell located in thesame central region, but also nerve regeneration that nerve out ofperikaryon located in peripheral region (for example, central fiber suchas olfactory nerve, dorsal root ganglion neuron) regenerates incircumstance of neuroaxis regeneration in central tissue. The nerveregeneration for nerve regeneration in peripheral nerve includes, notonly nerve regeneration that the perikaryon located in peripheral regionputs out axon which extends in peripheral tissue, but also nerveregeneration that nerve out of perikaryon located in central region suchas brain and spinal cord regenerates in circumstance of peripheraltissue. The latter includes, for example, promoting activity of nerveregeneration in spinal cord motor nerve, and preganglionic neuron inautonomic nervous system of sympathetic nerve/parasympathetic nerve. Inaddition, it also includes promoting activity of nerve regenerationinvolved in the above both nerves such as sciatic nerve.

The growth cone collapse activity of semaphorin means the activity toabolish the growth cone observed in the culture prepared in thefollowing process: cultivating nerve cell (in general, a tissue fragmentof ganglion) in vitro for a given period, getting the extended neuriteand the growth cone in the tip of the neurite to be in an observablestate, then adding semaphorin having a give concentration (for example,about 3 units/mL; in which 1 unit/mL means the concentration ofsemaphorin to retract the growth cone in 50%) thereto, and continuingthe cultivation additionally for a given period (for example, one hour).In order to get the extended neurite and the growth cone in the tip ofthe neurite to be in an observable state, the in vitro cultivation ofnerve cell is done generally for 10 hours to 20 hours, but it may besuitably changed depending on the kind of the nerve and the condition ofcultivation. In this experiment, for example, if semaphorin is added tothe medium 1-60 minutes after a compound having a certain concentrationis added thereto, and the growth cone collapse caused by semaphorin issuppressed, it can be assessed that the compound is a semaphorininhibitor, in particular, a compound having the suppressing action onthe growth cone collapse activity caused by semaphorin.

And, the nerve outgrowth inhibitory activity in a collagen gel ofsemaphorin means, for example, a nerve outgrowth inhibitory activityobserved in a collagen gel containing both of semaphorin-producing celland nerve cell (generally, ganglion). The suppressing action on theneuronal outgrowth inhibitory activity is assessed by cultivatingsemaphorin-producing cell close to nerve cell in a collagen gel, keepingthe culture generally for more than one overnight, and then observingthe neurite outgrowth therein.

The semaphorin in the present invention means a collective term ofproteins having a similar semaphorin domain structure composed of about500 amino acid residues, more than about 20 proteins of which have beenreported until now, but the present invention should not be limited tothese known semaphorins. The semaphorin in the present inventionincludes semaphorins of mammal such as human being, preferably class 3,4, 5 or 6 semaphorins which are defined in literatures, more preferablyclass 3 or 6 semaphorins. The class 3 semaphorins include semaphorin 3A,and the class 6 semaphorins include semaphorin 6C. The gene sequenceinformation encoding these semaphorins is published in GenBank databaseor known literatures.

The pharmaceutical composition comprising the compound of formula (1) ora pharmaceutically acceptable salt thereof as an active ingredient maybe transformed with suitable additives to a drug formulation and beadministered orally or parenterally. The method for parenteraladministration includes, for example, transdermal, transnasal,injectable, ophthalmic, and internal. The formulation for oraladministration includes, for example, tablet, pill, powder, granule,capsule, syrup, emulsion, liquid, and suspension. And the formulationfor parenteral administration includes, for example, intramuscularinjection, subcutaneous injection, intradermal injection, eye drop, eyeointment, endermic liniment (such as ointment, lotion, and cream), nasaldrop (spray for nasal administration), patch, and suppository. Theliquid formulation can be suitably selected to solution, emulsion,suspension, or the like. The formulation of the present invention can beprepared with pharmaceutically acceptable additives in a known manner.

The above-mentioned additives include a pharmaceutically acceptableconventional carrier, and according to the intended use, an excipient, adisintegrant, a diluent, a pH adjuster, an isotonic agent, a binder, afluidizer, a lubricant, a coating agent, a solubilizer, a solubilizingagent, a thickener, a dispersant, a stabilizing agent, a sweeteningagent, a surfactant, an emulsifying agent, a flavor, etc. can be used.The additive used herein includes, for example, lactose, mannitol,microcrystalline cellulose, low-substituted hydroxypropylcellulose,cornstarch, partially-pregelatinized starch, carmellose calcium,croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearylfumarate, polyethylene glycol, propylene glycol, titanium oxide, talc,and the like.

The dose and the administration frequency can depend on theadministration route and patient's age, body weight, condition, etc.,but it is preferable to administer the drug formulation topically tolesion site. It is preferable to administer the drug once a day, or twoor more a day. When the drug is administered two or more times, it ispreferable to do repeatedly in days or in suitable intervals. It takesgenerally more than several days to several months to regenerate nerve,thus it is preferable to administer the drug continually in the therapyduration to inhibit the semaphorin action.

In case of sustained-release formulation, it is not necessary toadminister the drug repeatedly as long as the drug is sustainablyreleased after the administration.

The dose for an adult can be 50 μg-2 g, preferably 5 mg-100 mg per day,as the amount of the active ingredient, and can be administered once orin portions a day. In order to reduce the administration frequency, itis possible to use a sustained-release formulation, or administer thedrug gradually for a long time by using an osmotic pump. When the drugis parenterally administered, the dose for an adult can be 0.01 mg-100mg a day, more preferably 0.1 mg-50 mg a day, and can be administeredonce or in portions a day. In particular, as for eye drop, the dailydose of the active ingredient includes 0.01-10 mg a day, preferably 0.1mg-1 mg a day. In case of sustained-release formulation, the dose to beadministered can be adjusted so that the daily releasing amount can bein the above-mentioned range, thereby it is possible to reduce theadministration frequency.

In case of eye drop, the formulation can be administered in 0.01 w/v%-10 w/v %, preferably 0.05 w/v %-5 w/v % to an adult patient, andpreferably 1-several drops for one administration, 1-6 times a day,depending on the patient's condition. And in case of eye ointment, theformulation can be administered in 0.01 w/w %-10 w/w %, preferably 0.1w/w %-5 w/w %, and preferably 1-6 times a day, depending on thepatient's condition.

For any administration methods, it is preferable to choose theadministration route and the administration details to make the drugconcentration enough to inhibit semaphorin action in the therapy site.

In addition, the utility of the present medicament for treatment orprevention should not be limited to drugs for treatment or prevention ofneuropathy disorder and/or neurodegenerative disease, that is, it can beused as a veterinary drug, and additionally as an experimental reagentwhich is industrially important as an inhibitor of semaphorin signal.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Reference examples, Examples, and Tests; however, thetechnical scope of the present invention is not limited to such Examplesand the like. Each compound was identified with high-performance liquidchromatograph-mass spectrometer, LCMS, NMR spectrum, high-performanceliquid chromatography (HPLC), and other instruments.

In the following Reference examples, Examples, and Tables in Examples,the abbreviations shown below may be sometimes used to simplify thedescription of the present specification. The abbreviations in thesubstituents mean as follows: Me: methyl, Bu: butyl, tBu: tert-butyl,Ac: acetyl, Piv: pivaloyl, MOM: methoxymethyl, TMS: trimethylsilyl. Theabbreviations in the solvents mean as follows: DMF:N,N-dimethylformamide, NMP: N-methyl-2-pyrrolidone, THF:tetrahydrofuran. The abbreviations in the NMR data mean as follows: s:singlet, d: doublet, dd: double doublet, t: triplet, td: triple doublet,q: quartet, m: multiplet, br: broad, brs: broad singlet, brm: broadmultiplet, and J: coupling constant. The abbreviation in the LC/MSmeans, Rt: retention time.

High-performance liquid chromatography-mass spectrometer: the measuringcondition of LCMS is shown below, and the detected value of massspectrography [MS (m/z)] is shown as M+H.

Condition (1)

MS detector: ACQUITY SQD

HPLC: ACQUITY UPLC Column: ACQUITY UPLC BEH C18 1.7 μm, 2.1×50 mm

Flow rate: 0.75 mL/minWave length: 254 nmMobile phase: A: 0.05% aqueous formic acid

B: acetonitrile

Time program:

Step Time (min) 1 0.0-1.3 A:B = 90:10 => 1:99 2 1.3-1.5 A:B = 1:99 31.5-2.0 A:B = 90:10

Condition (2)

MS detector: SHIMADZU SPD-M20A

HPLC: SHIMADZU LCMS-2020 Column: Kinetix 1.7u C-18 100A

Flow rate: 0.50 mL/minWave length: 220, 254 nmMobile phase: A: 0.05% aqueous formic acid

B: acetonitrile

Time program:

Step Time (min) 1 0.0-1.7 A:B = 90:10 => 1:99 2 1.7-1.9 A:B = 1:99 31.9-3.0 A:B = 90:10

Condition (3)

MS detector: ACQUITY SQD

HPLC: Waters ACQUITY UltraPerformance LC Column: ACQITY UPLC BEH C18 1.7μm 2.1×30 mm

Flow rate: 0.80 mL/minWave length: 254 nmMobile phase: A: 0.05% aqueous formic acid

B: acetonitrile

Time program:

Step Time (min) 1 0.0-1.3 A:B = 90:10 => 1:99 2 1.3-1.5 A:B = 1:99 31.5-2.0 A:B = 90:10

Reference Example 1

According to a literature (Angew. Chem. Int. Ed., 52, p 3421-3424(2013)), Compound (a-1) was synthesized. The prepared Compound (a-1)(5.3 g, 10 mmol) was dissolved in tetrahydrofuran (30 mL), and themixture was cooled to −78° C. To the cooled mixture was added 2 mol/Lisopropylmagnesium chloride solution (5.5 mL, 11 mmol). The mixture wasstirred at −78° C. for 30 minutes, and then tributyltin chloride (3.3mL, 12 mmol) was added thereto. The reaction mixture was stirred at −78°C. for one hour. Water was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate, and concentrated in vacuo. The obtained residue waspurified by silica gel column chromatography (hexane:ethylacetate=90:10-5:95) to give Compound (a-2) (3.7 g, 53% yield).

¹H-NMR (CDCl₃, 300 MHz) δ: 7.40 (s, 1H), 7.08 (s, 1H), 5.18 (s, 2H),3.42 (s, 3H), 1.57 (s, 9H), 1.45-1.56 (m, 6H), 1.35 (s, 9H), 1.22-1.33(m, 6H), 1.06-1.00 (m, 6H), 0.86 (t, J=7.5 Hz, 9H).

Reference Example 2

Compound (a-1) (21.28 g, 40.0 mmol) was dissolved in tetrahydrofuran(100 mL), and the solution was cooled in acetone-dry ice bath. To thesolution was added 1.3 mol/L isopropylmagnesium chloride-lithiumchloride/tetrahydrofuran solution (43.1 mL, 56.0 mmol) dropwise over 15minutes, and the mixture was stirred for 15 minutes. To the mixture wasadded trimethyl borate (10.4 g, 100 mmol) dropwise, and the mixture waswarmed to room temperature. 5% Aqueous ammonium chloride (280 mL) wasadded thereto, and the mixture was extracted with a mixture of toluene(240 mL) and ethyl acetate (50 mL). The organic layer was washed withwater, and concentrated in vacuo to dryness. The obtained crude productwas stirred in toluene (30 g) to obtain a suspension, and the suspensionwas filtrated. The product on the filter was dried to give Compound(b-1) (15.8 g, 88% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.24 (s, 1H), 7.19 (s, 1H), 6.85-6.70 (brs,2H), 5.22 (s, 2H), 3.43 (s, 3H), 1.60 (s, 9H), 1.36 (s, 9H).

Reference Example 3

Compound (a-1) (63.88 g, 120 mmol) was suspended in toluene (255 g), andtrifluoroacetic acid (410 g, 3.60 mol) was added to the suspension. Thesuspension was stirred at room temperature for one hour, warmed to 50°C., and then stood at the same temperature for 2.5 hours to deposit acrystal. The suspension was cooled in ice bath and the precipitatedcrystal was collected on a filter. The crystal was washed with toluene(250 mL) and acetonitrile (250 mL), and dried in vacuo to give Compound(c-1) (29.97 g, 71.8% yield).

¹H-NMR (DMSO-de, 400 MHz); 13.5-12.0 (brs, 1H), 11.37 (s, 1H), 9.41(brs, 1H), 8.63 (s, 1H), 6.92 (s, 1H).

Reference Example 4

Compound (c-1) (13.92 g, 40.0 mmol) was suspended in dichloromethane(200 mL), and dry N,N-dimethylformamide (7.7 mL, 100 mmol) was added tothe suspension. To the ice-cooled suspension were added oxalyl chloride(7.11 g, 56.0 mol) dropwise over 20 minutes, and then additional oxalylchloride (2.03 g, 16.0 mmol) dropwise. After stirring the mixture for 30minutes, (2-trimethylsilyl)ethanol (25.0 g, 280 mmol) was added dropwisethereto. After stirring the mixture for 20 minutes, the reaction mixturewas concentrated in vacuo to remove about 50 mL of the solvent. To theconcentrated residue was added toluene (50 mL), and the mixture wascooled in ice bath. The mixture was filtrated and washed with a smallamount of dichloromethane. The filtrate was cooled in ice bath, andN,N-diisopropylethylamine (65.16 g, 504 mmol) and chloromethyl methylether (24.2 g, 300 mmol) were added dropwise to the filtrate. Water (100mL) was added thereto, and the mixture was concentrated in vacuo toremove most of the dichloromethane. To the concentrated mixture wereadded toluene (150 mL) and water (50 mL), and the mixture was separatedwith a separating funnel. The aqueous layer was extracted with toluene(100 mL). The combined organic layer was washed with water, andconcentrated in vacuo. To the residual liquid was added n-heptane (100mL), and the precipitated crystal was collected on a filter. To theobtained crude crystal (18.95 g) was added 2-propanol (55.7 g), and themixture was heated at about 60° C. to be dissolved. Then, water (27.8 g)was added dropwise thereto. The obtained homogeneous solution was cooledto deposit a crystal. The suspension was cooled and the precipitatedcrystal was collected on a filter. The crystal was washed with 67%aqueous 2-propanol, and dried in vacuo to give Compound (c-2) (14.25 g,67% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.19 (s, 1H), 7.21 (s, 1H), 5.31 (s, 2H),5.18 (s, 2H), 4.65-4.50 (m, 2H), 3.58 (s, 3H), 3.51 (s, 3H), 1.20-1.10(m, 2H), 0.07 (s, 9H).

Reference Example 5

A solution of Compound (c-2) (9.84 g, 18.4 mmol) in dry tetrahydrofuran(100 mL) was cooled in acetone-dry ice bath. To the solution was added1.3 mol/L isopropylmagnesium chloride-lithium chloride/tetrahydrofuransolution (20.0 mL, 26.0 mmol) dropwise, and the mixture was stirred for40 minutes. To the mixture was added trimethyl borate (5.72 g, 55.1mmol) dropwise, and the mixture was warmed to room temperature. 2%Aqueous ammonium chloride (120 mL) was added thereto, and most of thetetrahydrofuran was removed out by the concentration in vacuo. Themixture was extracted with ethyl acetate (150 mL), and the organic layerwas washed with water (100 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo to dryness. The obtained crude product wasre-crystallized from ethyl acetate-heptane to give Compound (c-3) (5.89g, 71% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.46 (s, 1H), 8.41 (s, 1H), 7.41 (s, 1H),5.44 (s, 2H), 5.12 (s, 2H), 4.45-4.30 (m, 2H), 3.46 (s, 3H), 3.44 (s,3H), 1.10-1.00 (m, 2H), 0.03 (s, 9H).

Reference Example 6

To a solution of 2-bromoacetic acid (1.7 g, 12 mmol) inN,N-dimethylformamide (12 mL) was added sodium azide (0.78 g, 12 mmol).The mixture was stirred at room temperature for 16 hours, and thenN,N′-diisopropylcarbodiimide (0.76 g, 6.0 mmol) was added thereto. Afterstirring the reaction mixture at room temperature for one hour,di-tert-butyl L-glutamate hydrochloride (0.89 g, 3.0 mmol) anddiisopropylethylamine (0.51 mL, 3.0 mmol) were added thereto. Afterstirring the reaction mixture at room temperature for 8 hours, water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, and then concentrated in vacuo. The obtained residue waspurified by silica gel column chromatography (hexane:ethylacetate=90:10-50:50) to give Compound (d-2) (0.87 g, 85% yield).

¹H-NMR (CDCl₃, 300 MHz) δ: 6.98-6.94 (br, 1H), 4.44-4.51 (m, 1H), 3.98(s, 2H), 1.88-2.32 (m, 4H), 1.46 (s, 9H), 1.43 (s, 9H).

Reference Example 7

To a solution of Compound (d-2) (1.71 g, 5.00 mmol) in NMP (5 mL) wasadded propargyl alcohol (390 mg, 6.00 mmol). To the mixture were added asolution of copper sulfate pentahydrate (62 mg, 0.250 mmol) in water (1mL), and then sodium ascorbate (99 mg, 0.500 mmol). The reaction mixturewas stirred at room temperature. After one hour, water was addedthereto, and the mixture was extracted with chloroform 3 times. Thecombined organic layer was washed with water, and concentrated in vacuoto dryness. The obtained crude product was purified by silica gel columnchromatography (chloroform—methanol) to give Compound (d-3) (1.84 g, 92%yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.72 (s, 1H), 6.80 (d, J=7.6 Hz, 1H), 5.10(d, J=16.4 Hz, 1H), 5.05 (d, J=16.4 Hz, 1H), 4.82 (s, 2H), 4.46 (ddd,J=8.0, 8.0, 4.8 Hz, 1H), 2.32-2.20 (m, 2H), 2.15-2.05 (m, 1H), 1.95-1.85(m, 1H), 1.45 (s, 9H), 1.44 (s, 9H). 20 [0255]

Reference Example 8

To a solution of Compound (d-3) (1.25 g, 3.14 mmol) in dichloromethane(15 mL) was added triethylamine (0.65 g, 5.02 mmol) at ice temperature,then methanesulfonyl chloride (0.47 g, 4.08 mmol) dropwise. After 30minutes, water (10 mL) was added thereto, and the organic layer wasseparated out. The aqueous layer was extracted with dichloromethane (10mL), and the combined organic layer was concentrated in vacuo todryness. The obtained crude product was purified by silica gel columnchromatography (chloroform—ethyl acetate) to give Compound (d-4) (1.13g, 75.6% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.92 (s, 1H), 6.83 (d, J=7.2 Hz, 1H), 5.40(s, 2H), 5.12 (d, J=16.4 Hz, 1H), 5.08 (d, J=16.4 Hz, 1H), 4.45 (ddd,J=4.8, 4.8, 2.0 Hz, 1H), 3.03 (s, 3H), 2.40-1.90 (m, 4H), 1.46 (s, 9H),1.44 (s, 9H).

Reference Example 9

According to the method described in Reference example 6, provided thattert-butyl N-ω-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine(1.3 g, 3.0 mmol) was used instead of di-tert-butyl glutamatehydrochloride (0.89 g, 3.0 mmol), Compound (e-1) was prepared (1.0 g,63% yield).

¹H-NMR (CDCl₃, 300 MHz) δ: 7.00-7.03 (br, 1H), 6.51 (s, 1H), 6.11-6.02(br, 3H), 4.37-4.44 (m, 1H), 3.98 (s, 2H), 3.80 (s, 3H), 3.19-3.31 (m,2H), 2.67 (s, 3H), 2.59 (s, 3H), 2.15 (s, 3H), 1.52-1.88 (m, 4H), 1.45(s, 9H).

Reference Example 10

di-tert-Butyl glutamate hydrochloride (0.70 g, 2.3 mmol) was dissolvedin chloroform (11 mL), and then bromoacetyl bromide (0.43 g, 2.2 mmol)was added thereto. After stirring the reaction mixture at roomtemperature for 3 hours, saturated aqueous ammonium chloride was addedto the reaction mixture, and the mixture was extracted with chloroform.The organic layer was washed with brine, dried over sodium sulfate, andthen concentrated in vacuo. The obtained residue was purified by silicagel column chromatography (chloroform:methanol=100:0-98:2) to giveCompound (f-2) (0.82 g, 100% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.09 (d, J=7.8 Hz, 1H), 4.47 (td, J=7.8, 4.6Hz, 1H), 3.88 (s, 2H), 2.38-2.13 (m, 3H), 2.00-1.91 (m, 1H), 1.48 (s,9H), 1.45 (s, 9H).

Reference Example 11

To a solution of 2′-amino-4′,5′-dimethoxyacetophenone (4.9 g, 25 mmol)in dimethoxyethane (150 mL) was added sodium methoxide (7.5 g, 0.14mol), and the reaction mixture was stirred at room temperature for 30minutes. Ethyl formate (12 mL, 0.15 mol) was added thereto. Afterstirring the reaction mixture at room temperature for 2 hours, 2 mol/Lhydrochloric acid (25 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate, and then concentrated invacuo. To the residue was added 4 mol/L hydrogen chloride in dioxane (30mL). After stirring the reaction mixture at 50° C. for one hour, thereaction mixture was cooled to room temperature, and the generated solidwas collected on a filter and dried to give Compound (A-2) (3.5 g, 68%yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=206/0.42 min

Reference Example 12

Compound (A-2) (2.0 g, 9.8 mmol) was dissolved in 2 mol/L aqueous sodiumhydroxide (20 mL), and then iodine (3.0 g, 12 mmol) in 20% aqueouspotassium iodide (20 mL) was added thereto. After stirring the reactionmixture at room temperature for one hour, the reaction mixture wasneutralized with acetic acid, and the generated solid was collected on afilter. The obtained solid was washed with ethanol and dried to giveCompound (A-3) (2.2 g, 68% yield).

LC/MS (Condition (1)): [M+H]+/Rt=331/0.55 min

Reference Example 13

To a solution of Compound (A-3) (1.50 g, 4.5 mmol) inN,N-dimethylformamide (20 mL) were added cesium carbonate (2.2 g, 6.8mmol) and methyl iodide (1.4 mL, 23 mmol), and the reaction mixture wasstirred at room temperature for one hour. Water was added to thereaction solution, and the generated solid was collected on a filter.The obtained crude product was washed with ethanol to give Compound(A-4) (1.2 g, 78% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=345/0.63 min

Reference Example 14

To a solution of Compound (A-4) (17 mg, 50 nmol) inN,N-dimethylformamide (0.5 mL) were added toluene (0.5 mL), Compound(a-2) (35 mg, 50 nmol), potassium carbonate (35 mg, 0.25 mmol), copperiodide (1.0 mg, 5.0 nmol), and tetrakis(triphenylphosphine)palladium(2.9 mg, 2.5 nmol). After stirring the reaction mixture at 100° C. undernitrogen atmosphere for 2 hours, the reaction mixture was cooled to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate, and then concentrated in vacuo. Theobtained residue was purified by silica gel column chromatography(chloroform:methanol=99:1-80:20) to give Compound (A-5) (10 mg, 32%yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=624/1.13 min

Example 13-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid

To a solution of Compound (A-5) (10 mg, 16 nmol) in chloroform (1 mL)was added boron tribromide (1 mol/L dichloromethane solution) (1 mL, 1mmol). After stirring the reaction mixture at room temperature for onehour, methanol and toluene were added to the reaction mixture, and waterin the mixture was removed by azeotropy to obtain a dried residue. Theobtained crude product was washed with methanol to give the titlecompound (3 mg, 45% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=412/0.49 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.28 (brs, 1H), 10.21 (brs, 1H), 9.81(brs, 1H), 9.42 (brs, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 7.57 (s, 1H),6.99 (s, 1H), 6.94 (s, 1H), 3.82 (s, 3H).

Example 2 Prop-2-yn-1-yl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate

To a solution of the compound of Example 1 (10 mg, 24 nmol) in toluene(1 mL) was added thionyl chloride (1 mL), and the reaction mixture wasstirred at 80° C. for one hour. The reaction mixture was cooled to roomtemperature and concentrated in vacuo, and then a solution of propargylalcohol (0.1 mL, 1.73 mmol) in dichloromethane (0.5 mL) was added to theresidue. After stirring the reaction mixture at room temperature for onehour, toluene was added to the reaction mixture, and the mixture wasconcentrated in vacuo to give the title compound (11 mg, 93% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=450/0.54 min

¹H-NMR (DMSO-de, 400 MHz) δ: 8.58 (s, 1H), 8.22 (s, 1H), 7.56 (s, 1H),6.99 (s, 1H), 6.96 (s, 1H), 3.79 (s, 3H), 3.54-3.55 (m, 1H), 2.48-2.50(m, 2H).

Example 3N-({4-[({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid

Compound (d-2) (51 mg, 0.15 mmol) was dissolved in trifluoroaceticacid/water/triisopropylsilane (95/2.5/2.5) (1 mL), and the reactionmixture was stirred at room temperature for one hour and thenconcentrated in vacuo. The obtained residue was washed with diethylether, and dried. The obtained crude product was dissolved indimethylsulfoxide (0.2 mL), and then tert-butyl alcohol/water (95/5) (1mL), the compound of Example 2 (11 mg, 24 nmol),tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (0.005 mol/Ldimethylsulfoxide solution) (120 μL), 0.4 mol/L aqueous sodium ascorbate(60 μL), and 0.3 mol/L aqueous copper sulfate (30 μL) were added to thesolution. After stirring the reaction mixture at room temperature for 4hours, the reaction mixture was concentrated in vacuo. The obtainedresidue was purified by reverse phase chromatography with an ODS column(0.05% aqueous trifluoroacetic acid:acetonitrile) to give the titlecompound (2.7 mg, 17% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=680/0.44 min

¹H-NMR (CD₃OD) δ: 8.50 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.70 (s,1H), 7.05 (s, 1H), 6.97 (s, 1H), 5.48 (s, 2H), 5.21 (s, 2H), 4.38-4.44(m, 1H), 3.92 (s, 3H), 2.36-2.41 (m, 2H), 1.92-2.20 (m, 2H).

Example 4N²-({4-[({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-argininetrifluoroacetate

According to the method described in Example 3, the title compound (13mg) was prepared from the compound of Example 2 and Compound (e-1).

LC/MS (Condition (1)): [M+H]⁺/Rt=707/0.41 min

¹H-NMR (CD₃OD) δ: 8.42 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.67 (s,1H), 7.09 (s, 1H), 6.95 (s, 1H), 5.49 (s, 2H), 5.22 (brs, 2H), 4.33-4.36(m, 1H), 3.96 (s, 3H), 3.02-3.14 (m, 2H), 1.49-1.92 (m, 4H). 10 [0266]

Reference Example 15

To a slurry of Compound (A-4) (34.93 g, 101.0 mmol) in dichloromethane(1250 mL) was added boron tribromide (76.07 g, 303.0 mmol) dropwise atice temperature. After the heat generation from the reaction mixturestopped, the reaction mixture was heated to reflux for 8 hours and thenallowed to cool. The reaction mixture was cooled in ice bath, andmethanol (450 mL) was added dropwise thereto while the insidetemperature thereof was kept around 10° C. to terminate the reaction.The obtained homogeneous solution was concentrated in vacuo to drynesswith an evaporator. The residue was dissolved in methanol (750 mL) togive a homogeneous solution, and the homogeneous solution was heated toreflux for 15 minutes. The solution was concentrated in vacuo todryness, methanol (300 mL) and toluene (400 mL) were added to theresidue, and the solution was concentrated in vacuo again. To theresidue was added 2-propanol (50 mL), and the mixture was stirred togive a slurry. The solid in the slurry was collected on a filter, andwashed with toluene (100 mL) and ethyl acetate (100 mL). The obtainedwet cake was transferred to another flask, and was suspended with drydichloromethane (400 mL). The suspension was cooled in ice bath, andN,N-diisopropylethylamine (65 g, 506 mmol) and methoxymethyl chloride(25.0 g, 304 mmol) were added dropwise to the suspension. Aftercompleting the drop, the mixture was warmed to room temperature. Afterconfirming the termination of the reaction with a HPLC, water (300 mL)containing potassium hydrogensulfate (41 g) was added to the reactionmixture. The mixture was separated with a separating funnel. The aqueouslayer was re-extracted with dichloromethane (100 mL). The combinedorganic layer was washed with 0.1% aqueous sodium hydrogencarbonate (300mL), dried over anhydrous sodium sulfate, and concentrated in vacuo todryness. To the residue was added 125 mL of 2-propanol, and the solutionwas concentrated in vacuo to dryness. The procedure was repeated twice.To the residue was added 2-propanol (103 g), and the mixture was heatedto reflux, in which the crystal was not dissolved. The mixture wasgradually cooled over about 2 hours, and kept in ice bath for about 2hours. The crystal was collected on a filter, washed with 2-propanol (60mL), and dried in vacuo to give Compound (E-1) (33.93 g, 83.74 mmol).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.53 (s, 1H), 7.79 (s, 1H), 7.22 (s, 1H),5.43 (s, 2H), 5.29 (s, 2H), 3.81 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H).

Reference Example 16

To a mixture of Compound (c-3) (1.99 g, 4.38 mmol), Compound (E-1) (1.42g, 3.51 mmol), sodium carbonate (1.11 g, 10.52 mmol),bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(127 mg, 0.175 mmol) were added tetrahydrofuran (28 mL) and ionexchanged water (7 mL) under nitrogen atmosphere, and the reactionmixture was stirred in hot water bath (65° C.) for 1.5 hours. Afterconfirming the termination of the reaction with a HPLC, the reactionmixture was allowed to cool, and toluene (50 mL), ethyl acetate (25 mL),and water (50 mL) were added thereto. The mixture was separated with aseparating funnel. The organic layer was washed with water (50 mL), andconcentrated in vacuo to dryness. The residue was purified by silica gelcolumn chromatography to give Compound (E-2) (2.37 g, 3.45 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.34 (s, 1H), 8.80 (s, 1H), 8.17 (s, 1H),7.27 (s, 1H), 7.18 (s, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 5.32 (s, 2H),5.19 (s, 2H), 4.60 (brs, 1H), 4.49 (brs, 1H), 3.85 (s, 3H), 3.60 (s,3H), 3.56 (s, 3H), 3.54 (s, 3H), 3.52 (s, 3H), 1.20-1.10 (m, 2H), 0.06(s, 9H). 5 [0268]

Reference Example 17

To a solution of Compound (E-2) (2.4 g, 3.5 mmol) in tetrahydrofuran (12mL) was added 1 mol/L tetrabutylammonium fluoride in tetrahydrofuran(9.1 mL, 9.1 mmol) dropwise, and the reaction mixture was stirred atroom temperature for one hour. Subsequently, 1 mol/L tetrabutylammoniumfluoride in tetrahydrofuran (1.4 mL) was added thereto, and the reactionmixture was stirred at room temperature for one hour. And furthermore, 1mol/L tetrabutylammonium fluoride in tetrahydrofuran (1.75 mL) was addedthereto, and the reaction mixture was stirred at room temperature forone hour. To the reaction solution was added toluene dropwise, then themixture was cooled in ice bath. The precipitated solid was removed byfiltration. From the filtrate for crystallization, most of THF wasremoved by concentration in vacuo. 10% Aqueous sodium carbonate wasadded to the residue, and the aqueous layer was extracted with a mixtureof ethyl acetate-toluene (1:1). To the aqueous layer were added ethylacetate (10 mL), and concentrated hydrochloric acid to adjust the pH toabout 3-4, and then a crystal was precipitated. The mixture wasconcentrated in vacuo to remove ethyl acetate, and water was addedthereto. The mixture was stirred to give a suspension. The crystal wascollected on a filter, washed with water and acetonitrile, and dried invacuo to give Compound (E-3) (0.14 g, 6.6% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 13.04 (s, 1H), 8.83 (s, 1H), 8.40 (s, 1H),7.88 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 5.443 (s, 2H), 5.440 (s, 2H),5.29 (s, 2H), 5.13 (s, 2H), 3.86 (s, 3H), 3.50 (s, 3H), 3.47 (s, 3H),3.46 (s, 3H), 3.43 (s, 3H), 3.33 (s, 3H).

The carboxylic acid can be also prepared by dissolvingtetrabutylammonium salt thereof in water and adding hydrochloric acid tothe solution to precipitate the desired product.

Reference Example 18

To a solution of Compound (E-3) (147 mg, 0.250 mmol) in dichloromethane(5 mL) were added EDC (120 mg, 0.630 mmol), N-hydroxybenzotriazolemonohydrate (1.7 mg, 0.013 mmol), and di-tert-butyl glutamatehydrochloride (148 mg, 0.500 mmol), and then N,N-diisopropylethylamine(64.7 mg, 0.500 mmol) was added thereto. Two hours later, 1% aqueoushydrochloric acid (10 mL) was added to the reaction mixture, and themixture was separated with a separating funnel. The organic layer waswashed with 1% aqueous sodium hydrogencarbonate, and concentrated invacuo to dryness. The obtained crude product was purified by silica gelcolumn chromatography (chloroform—methanol) to give Compound (E-4) (126mg, 61% yield).

¹H-NMR (DMSO-d6, 400 MHz) (5:3 rotamer mixture at amide site) δ: 8.13(s, 0.62H), 8.08 (s, 0.38H), 7.78 (s, 0.62H), 7.75 (s, 0.38H), 7.26 (s,0.38H), 7.24 (s, 0.62H), 7.12 (s, 0.38H), 7.11 (s, 0.62H), 6.13 (s,0.62H), 6.03 (s, 0.38H), 5.45-5.20 (m, 8H), 4.49 (dd, J=10.0, 4.8 Hz,1H), 3.88 (s, 1.12H), 3.79 (s, 1.88H), 3.60-3.50 (m, 12H), 2.50-1.90 (m,4H), 1.48 (s, 5.62H), 1.33 (s, 3.38H), 1.31 (s, 3.38H), 1.27 (s, 5.62H).5 [0270]

Example 5N-{[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamicacid

Compound (E-4) (37 mg, 0.045 mmol) was dissolved in trifluoroacetic acid(1 mL), and the reaction mixture was stirred at room temperature for 3hours. The reaction solution was concentrated in vacuo by azeotropy withtoluene. The obtained residue was washed with acetonitrile to give theproduct (18 mg, 73% yield).

LC/MS (Condition (2)): [M+H]⁺/Rt=541/0.89 min

¹H-NMR (CD₃OD, 400 MHz) δ: 7.98 (s, 3/5H), 7.91 (brs, 2/5H), 7.69 (s,2/5H), 7.66 (s, 3/5H), 7.12 (s, 3/5H), 7.09 (s, 2/5H), 6.69 (s, 3/5H),6.69 (s, 2/5H), 5.84 (s, 2/5H), 5.67 (s, 3/5H), 3.97 (s, 9/5H), 3.92 (s,6/5H), 3.35-3.34 (m, 1H), 2.19-2.09 (m, 4H).

Reference Example 19

To a solution of Compound (E-3) (294 mg, 0.500 mmol) in dichloromethane(10 mL) were added EDC (288 mg, 1.25 mmol), N-hydroxybenzotriazolemonohydrate (3.4 mg, 0.025 mmol), and then propargylamine (103 mg, 1.88mmol). Six hours later, another EDC (48 mg, 0.25 mmol) was addedthereto, and mixture was reacted for more 4 hours. Water (30 mL) and 3%hydrochloric acid (5 mL) were added to the reaction mixture, and themixture was separated with a separating funnel. The organic layer waswashed with 3% aqueous sodium hydrogencarbonate, and water, andconcentrated in vacuo to dryness. The obtained crude product waspurified by silica gel column chromatography (chloroform-methanol) togive Compound (F-1) (46 mg, 15% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 9.21 (s, 1H), 8.73 (s, 1H), 8.14 (s, 1H),7.24 (s, 1H), 7.17 (s, 1H), 6.09 (m, 1H), 5.38 (s, 2H), 5.35 (s, 2H),5.30 (s, 2H), 5.18 (s, 2H), 4.37 (brs, 2H), 3.86 (brs, 3H), 3.61 (s,3H), 3.56 (s, 3H), 3.54 (s, 3H), 3.51 (s, 3H), 2.25 (t, J=2.4 Hz, 1H).

Example 63-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-N-(prop-2-yn-1-yl)-4H-chromene-5-carboxamide

According to the method described in Example 5, the title compound (6.7mg, 56%) was prepared from Compound (F-1) (17 mg, 0.027 mmol).

LC/MS (Condition (2)): [M+H]+/Rt=449/1.16 min

¹H-NMR (DMSO-de, 400 MHz) δ: 8.57 (s, 1H), 8.21 (t, J=5.4 Hz, 1H), 8.17(s, 1H), 7.56 (s, 1H), 6.92 (s, 1H), 6.92-6.90 (m, 1H), 3.98 (dd, J=5.4,2.6 Hz, 2H), 3.76 (s, 3H), 3.06 (t, J=2.6 Hz, 1H).

Reference Example 20

To a solution of 1-(2-amino-4,5-dimethoxyphenyl) ethanone (10 g, 51.2mmol) in THF (200 mL) was added triethylamine (10.37 g, 102 mmol), andthe reaction mixture was stirred. And, acetyl chloride (6.03 g, 77 mmol)was added thereto. After stirring the reaction mixture at roomtemperature for 2 hours, 10% aqueous potassium hydroxide was added tothe reaction mixture, and the mixture was extracted with chloroform. Theorganic layer was washed with brine, dried over sodium sulfate, and thenconcentrated in vacuo to give Compound (G-1) (12.15 g, 100%).

LC/MS (Condition (3)): [M+H]⁺/Rt=238/0.65 min 10 [0274]

Reference Example 21

Compound (G-1) (6.1 g, 25.7 mmol) was suspended in t-butanol (50 mL),and potassium t-butoxide (15.0 g, 134.0 mmol) was added thereto. Thereaction mixture was stirred at 90° C. for 8 hours. After the reactionwas completed, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, and then concentrated in vacuo. Theobtained residue was purified by silica gel column chromatography(chloroform:methanol=100:0-90:10) to give Compound (G-2) (4.17 g, 74%yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 11.37 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H),6.22 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.39 (s, 3H).

Reference Example 22

To a solution of Compound (G-2) (6.9 g, 31.5 mmol) in acetonitrile (300mL) was added N-iodosuccinimide (14.16 g, 62.9 mmol). After stirring thereaction mixture at 80° C. for 5 hours, the reaction mixture wasconcentrated. To the residue was added an aqueous solution of sodiumthiosulfate, and the mixture was stirred again for 30 minutes. Theprecipitated solid was collected on a filter, washed with water, anddried in vacuo to give Compound (G-3) (9.72 g, 89%).

¹H-NMR (DMSO-de, 400 MHz) δ: 11.86 (s, 1H), 7.21 (s, 1H), 6.88 (s, 1H),3.84 (s, 3H), 3.82 (s, 3H), 2.71 (s, 3H).

Reference Example 23

Compound (G-3) (0.9 g, 2.61 mmol) and cesium carbonate (1.27 g, 3.91mmol) were suspended in NMP (40 mL), and then iodomethane (0.81 mL,13.04 mmol) was added thereto. The reaction mixture was stirred at roomtemperature for 2 hours. After the reaction was completed, water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, and then concentrated in vacuo. The obtained residue waspurified by silica gel column chromatography (hexane:ethylacetate=5:95-20:80) to give Compound (G-4) (0.46 g, 49% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 7.29 (s, 1H), 7.00 (s, 1H), 3.94 (s, 3H),3.86 (s, 3H), 3.74 (s, 1H), 2.74 (s, 3H).

Reference Example 24

Compound (G-4) (0.46 g, 1.28 mmol) was suspended in dichloromethane (9mL), and boron tribromide (4.47 mL, 1.28 mmol) was slowly added thereto.The reaction mixture was stirred at room temperature for 2 hours. Afterthe reaction was completed, methanol was slowly added to the reactionmixture at 0° C., and the reaction mixture was stirred again for 30minutes and concentrated in vacuo. To the residue was added methanol,and the mixture was stirred for 30 minutes and then concentrated invacuo. To the residue was added methanol again, and the mixture wasstirred for 30 minutes and concentrated in vacuo to give Compound (G-5)(0.42 g, 100% yield).

LC/MS (Condition (3)): [M+H]⁺/Rt=332/0.59 min

Reference Example 25

To a solution of Compound (G-5) (0.33 g, 1.0 mmol) andN,N-diisopropylethylamine (1.75 mL, 10.0 mmol) in chloroform (4 mL) wasadded chloromethyl methyl ether (0.46 mL, 6.0 mmol) slowly, and then thereaction mixture was stirred at room temperature for 2 hours. After thereaction was completed, water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, and then concentrated in vacuo.The obtained residue was purified by silica gel column chromatography(chloroform:ethyl acetate=100:0-80:20) to give Compound (G-6) (0.38 g,90% yield).

LC/MS (Condition (3)): [M+H]⁺/Rt=420/0.85 min

Reference Example 26

To a solution of Compound (G-6) (73 mg, 0.17 mmol), Compound (b-1) (110mg, 0.24 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (12mg, 0.017 mmol) in THF (1.5 mL) was added sodium carbonate (92 mg, 0.87mmol), and then the reaction mixture was stirred at 65° C. undernitrogen atmosphere for 2 hours. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate, and thenconcentrated in vacuo. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=95:5-10:90) to give Compound(G-7) (111 mg, 91% yield).

LC/MS (Condition (3)): [M+H]⁺/Rt=698/1.15 min

Example 73-(6,7-Dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid

Compound (G-7) (111 mg, 0.16 mmol) was dissolved in a mixture of toluene(1 mL) and water (5.8 μl), and then trifluoroacetic acid (0.98 mL) wasadded thereto. The reaction mixture was stirred at 55° C. for 2 hours.The reaction solution was concentrated by azeotropy with toluene. Theobtained residue was washed with acetonitrile to give the title compound(28 mg, 41% yield).

LC/MS (Condition (3)): [M+H]⁺/Rt=426/0.513 min

¹H-NMR (DMSO-de, 400 MHz) δ: 12.84 (bs, 1H), 11.25 (s, 1H), 9.96 (s,1H), 9.53 (s, 1H), 9.24 (s, 1H), 8.08 (s, 1H), 7.16 (s, 1H), 6.97 (s,1H), 6.88 (s, 1H), 3.53 (s, 3H), 2.16 (s, 3H).

Reference Example 27

According to the method described in Reference example 26, Compound(H-1) (240 mg, 77%) was prepared from Compound (G-6) (186 mg, 0.44 mmol)and Compound (c-3) (214 mg, 0.47 mmol).

LC/MS (Condition (3)): [M+H]⁺/Rt=702/1.14 min

Reference Example 28

To a solution of Compound (H-1) (240 mg, 0.34 mmol) in THF (2 mL) wasadded tetrabutylammonium fluoride in THF (1 mol/L, 0.6 mmol, 0.60 mmol),and then the reaction mixture was stirred at room temperature for onehour. After the reaction was completed, the reaction mixture wasconcentrated in vacuo to give Compound (H-2) (0.71 g).

LC/MS (Condition (2)): [M+H]⁺/Rt=601/0.75 min

Reference Example 29

To a solution of Compound (H-2) (205 mg, 0.34 mmol) in acetonitrile (2mL) was added Compound (d-4) (212 mg, 0.45 mmol), and then the reactionmixture was stirred at room temperature for 18 hours. Saturated aqueousammonium chloride was added to the reaction mixture, and the mixture wasextracted with chloroform. The organic layer was washed with brine,dried over sodium sulfate, and then concentrated in vacuo. The obtainedresidue was purified by silica gel column chromatography(chloroform:ethyl acetate=95:5-15:85, followed bychloroform:methanol=9:1) to give Compound (H-3) (225 mg, 67% yield).

LC/MS (Condition (3)): [M+H]⁺/Rt=982/1.11 min

Example 8N-({4-[({[3-(6,7-Dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid

To a solution of Compound (H-3) (225 mg, 0.23 mmol) in acetic acid (4mL) was added hydrochloric acid (0.17 mL, 5.5 mmol) in acetic acid (4mL), and then the reaction mixture was stirred at room temperatureovernight. The reaction solution was concentrated by azeotropy withtoluene, and the residue was dried in vacuo. To the obtained residue wasadded toluene, and the insoluble matter was removed by filtration. Thefiltrate was concentrated to give the title compound (40 mg, 25% yield).

LC/MS (Condition (3)): [M+H]⁺/Rt=694/0.466 min

¹H-NMR (DMSO-de, 400 MHz) δ: 8.71 (d, J=7.3 Hz, 1H), 8.09-8.06 (m, 2H),7.17 (s, 1H), 7.01 (s, 1H), 6.89 (s, 1H), 5.41-5.03 (m, 4H), 4.26-4.20(m, 1H), 3.52 (s, 3H), 2.33-2.27 (m, 2H), 2.16 (s, 3H), 2.07-1.92 (m,2H).

Reference Example 30

To a solution of esculetin (1.78 g, 10 mmol) in chloroform (100 mL) wereadded diisopropylethylamine (8.3 mL, 50 mmol) and chloromethyl methylether (2.3 mL, 30 mmol), and then the reaction mixture was stirred atroom temperature for one hour. Water was added to the reaction mixture,and the mixture was extracted with chloroform. The organic layer waswashed with brine, dried over magnesium sulfate, and then concentratedin vacuo. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=90:10-5:95) to give Compound (I-2)(2.6 g, 98% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=267/0.76 min

Reference Example 31

To a solution of Compound (I-2) (2.6 g, 9.8 mmol) in acetic acid (50 mL)were added sodium acetate (2.5 g, 30 mmol) and bromine (0.66 mL, 13mmol), and then the reaction mixture was stirred at room temperature forone hour. To the reaction mixture was added water, and the precipitatedsolid was collected on a filter, washed with water, and dried to giveCompound (I-3) (3.0 g, 87% yield).

LC/MS (Condition (1)): [M+H]+/Rt=344/0.93 min

Reference Example 32

To a solution of Compound (I-3) (0.44 g, 1.27 mmol) inN,N-dimethylformamide (6.33 mL) were added Compound (a-2) (0.44 g, 0.63mmol), copper iodide (12 mg, 0.063 mmol), andtetrakis(triphenylphosphine)palladium (37 mg, 0.032 mmol). Afterstirring the reaction mixture at 80° C. under nitrogen atmosphere for 2hours, the reaction mixture was cooled to room temperature, water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, and then concentrated in vacuo. The obtained residue waspurified by silica gel column chromatography (hexane:ethylacetate=90:10-5:95) to give Compound (I-4) (0.18 g, 42% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=671/1.27 min

Example 96,6′,7,7′-Tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylicacid

Compound (I-4)(0.18 g, 0.27 mmol) was dissolved in trifluoroacetic acid(5 mL), and then the reaction mixture was stirred at room temperaturefor one hour, and concentrated in vacuo. The obtained crude product waswashed with diethyl ether to give the title compound (0.10 g, 94%yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=399/0.56 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.34 (brs, 1H), 10.29 (brs, 1H), 9.45(brs, 1H), 9.39 (brs, 1H), 8.44 (s, 1H), 8.04 (s, 1H), 7.01 (s, 1H),6.94 (s, 1H), 6.77 (s, 1H).

Example 10 Prop-2-yn-1-yl6,6′,7,7′-tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromene-5′-carboxylate

According to the method described in Example 2, the title compound (70mg, 64% yield) was prepared from the compound of Example 9 (0.10 g, 0.25mmol).

LC/MS (Condition (1)): [M+H]⁺/Rt=437/0.61 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.52 (s, 1H), 10.30 (s, 1H), 9.64 (s, 1H),9.45 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.01 (s, 1H), 7.00 (s, 1H),6.77 (s, 1H), 3.55-3.56 (m, 1H), 2.52-2.55 (m, 2H).

Example 11N-{[4-({[(6,6′,7,7′-Tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-glutamicacid

According to the method described in Example 3, the title compound (6.5mg, 39%) was prepared from the compound of Example 10 (11 mg, 0.025mmol).

LC/MS (Condition (1)): [M+H]⁺/Rt=667/0.51 min

¹H-NMR (CD₃OD) δ: 8.43 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.04 (s,1H), 6.96 (s, 1H), 6.78 (s, 1H), 5.49 (s, 2H), 5.22 (s, 2H), 4.40-4.43(m, 1H), 2.38 (t, J=7.6 Hz, 2H), 1.91-2.20 (m, 2H). 10 [0291]

Example 12N²-{[4-({[(6,6′,7,7′-Tetrahydroxy-2,4′-dioxo-2H,4′H-3,3′-bichromen-5′-yl)carbonyl]oxy}methyl)-1H-1,2,3-triazol-1-yl]acetyl}-L-argininetrifluoroacetate

According to the method described in Example 3, the title compound (2.8mg) was prepared from the compound of Example 2 and the compound ofExample 10 (26 mg, 0.050 mmol).

LC/MS (Condition (1)): [M+H]⁺/Rt=694/0.45 min

¹H-NMR (CD₃OD) δ: 8.43 (s, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.06 (s,1H), 6.98 (s, 1H), 6.79 (s, 1H), 5.51 (s, 2H), 5.23 (brs, 2H), 4.33-4.38(m, 1H), 3.02-3.14 (m, 2H), 1.49-1.92 (m, 4H).

Reference Example 33

6,7-Dimethoxyquinolin-2(1H)-one (M-1) (2.8 g, 14 mmol) which wasprepared according to a literature (Heterocycles, 65, p 2095 (2005)) wasdissolved in DMF (100 mL), and N-bromosuccinimide (2.4 g, 14 mmol) wasadded thereto. The mixture was stirred at room temperature for one hour.Ice in water (100 mL) was added to the mixture at 0° C., and theprecipitated solid was collected by suction filtration to give Compound(M-2) (3.3 g, 84% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.12 (s, 1H), 6.89 (s, 1H), 6.86 (s, 1H),4.02-4.00 (m, 3H), 3.93 (s, 3H).

Reference Example 34

To a suspension of sodium hydride (172 mg, 4.3 mmol) in DMF (14 mL) wasadded Compound (M-2) (0.41 g, 1.4 mmol) at 0° C., and then the reactionmixture was stirred at the same temperature for 30 minutes. Iodomethane(0.27 mL, 4.3 mmol) was added to the reaction mixture at 0° C., and themixture was stirred at room temperature for one hour. A saturated watersolution of ammonium chloride was added to the mixture at 0° C., and theprecipitated solid was collected by suction filtration, washed withwater, and dried to give Compound (M-3) (0.22 g, 52% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.03 (s, 1H), 6.90 (s, 1H), 6.76 (s, 1H),4.02 (s, 3H), 3.94 (s, 3H), 3.81 (s, 3H).

Reference Example 35

To a solution of Compound (M-3) (0.17 g, 0.58 mmol) in methylenechloride (4.5 mL) was added 1 mol/L boron tribromide in methylenechloride (3.0 mL, 3.0 mmol) at 0° C., and then the reaction mixture wasstirred at room temperature for one hour. Methanol was added to thereaction mixture at 0° C., and the mixture was stirred until smokegeneration stopped. The mixture was concentrated in vacuo. The obtainedresidue was dissolved in chloroform (7 mL), andN,N-diisopropylethylamine (0.99 mL, 5.8 mmol) and chloromethyl methylether (0.26 mL, 3.5 mmol) were added at 0° C. to the solution. Afterstirring the reaction mixture at room temperature for 4 hours, water wasadded to the reaction mixture, and the mixture was extracted withchloroform. The organic layer was washed with brine, dried overmagnesium sulfate, and then concentrated in vacuo. The obtained residuewas purified by silica gel column chromatography (chloroform:ethylacetate=67:33-0:100) to give Compound (M-4) (0.12 g, 57% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.02 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H),5.36 (s, 2H), 5.26 (s, 2H), 3.77 (s, 3H), 3.56 (s, 3H), 3.54 (s, 3H).

Reference Example 36

According to the method described in Reference example 26, Compound(M-5) (24 mg, 42% yield) was prepared from Compound (M-4) (30 mg, 0.083mmol) and Compound (b-1) (52 mg, 0.12 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 1.39 (s, 9H), 1.62 (s, 9H), 3.46 (s, 3H),3.55 (s, 3H), 3.56 (s, 3H), 3.73 (s, 3H), 5.24 (s, 2H), 5.27 (s, 2H),5.37 (s, 2H), 7.15 (s, 1H), 7.21 (s, 1H), 7.39 (s, 1H), 8.33 (s, 1H),8.71 (s, 1H). 10 [0296]

Example 133-(6,7-Dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid

According to the method described in Example 5, the title compound (15mg, 100% yield) was prepared from Compound (M-5) (24 mg, 0.034 mmol).

LC/MS (Condition (2)): [M+H]+/Rt=412/1.32 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.27 (s, 1H), 9.98 (s, 1H), 9.43 (s, 1H),9.30 (s, 1H), 8.43 (s, 1H), 7.87 (s, 1H), 7.03 (s, 1H), 6.95 (s, 1H),6.86 (s, 1H), 3.56 (s, 3H). 5 [0297]

Reference Example 37

According to the method described in Reference example 26, Compound(N-1) (0.18 g, 80% yield) was prepared from Compound (M-4) (0.12 g, 0.33mmol) and Compound (c-3) (0.20 g, 0.43 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.78 (s, 1H), 8.38 (s, 1H), 7.41 (s, 1H),7.26 (s, 1H), 7.15 (s, 1H), 5.37 (s, 2H), 5.32 (s, 2H), 5.27 (s, 2H),5.19 (s, 2H), 4.60 (brs, 1H), 4.48 (brs, 1H), 3.73 (s, 3H), 3.60 (s,3H), 3.56 (s, 3H), 3.55 (s, 3H), 3.52 (s, 3H), 1.17-1.14 (brm, 2H), 0.05(s, 9H).

Reference Example 38

According to the method described in Reference example 28, Compound(N-2) (0.39 g) was prepared from Compound (N-1) (0.18 g, 0.27 mmol).

LC/MS (Condition (1)): [M+H]⁺/Rt=588/1.68 min

Reference Example 39

According to the method described in Reference example 29, Compound(N-3) (15 mg, 11% yield) was prepared from Compound (N-2) (110 mg, 0.17mmol) and Compound (d-4) (82 mg, 0.17 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.64 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H),7.50 (s, 1H), 7.16 (s, 1H), 6.83 (d, J=7.3 Hz, 1H), 5.70 (brs, 1H), 5.53(brs, 1H), 5.37 (s, 2H), 5.31 (s, 2H), 5.30 (brs, 2H), 5.15 (s, 2H),5.09 (s, 2H), 4.40-4.35 (brm, 1H), 3.73 (s, 3H), 3.56 (s, 3H), 3.56 (s,3H), 3.55 (s, 3H), 3.51 (s, 3H), 2.22-2.17 (brm, 2H), 1.79 (td, J=14.4,8.2 Hz, 2H), 1.40 (s, 18H).

Example 14N-({4-[({[3-(6,7-Dihydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid

To a solution of Compound (N-3) (15 mg) in acetic acid (0.3 mL) wasadded 36% hydrochloric acid (50 μl, 0.59 mmol) at 0° C., and then thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated in vacuo and the residue was purifiedby reverse phase chromatography with an ODS column (0.05% aqueoustrifluoroacetic acid/0.035% trifluoroacetic acid in acetonitrile) togive the title compound (2.5 mg, 24% yield).

LC/MS (Condition (2)): [M+H]⁺/Rt=680/1.28 min

¹H-NMR (CD₃OD, 400 MHz) δ: 8.33 (d, J=1.8 Hz, 1H), 8.20 (brs, 1H), 7.91(brs, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.98 (s, 2H), 5.49 (s, 2H), 5.23 (s,2H), 4.46-4.42 (m, 1H), 3.73 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 2.23-2.14(m, 1H), 1.98-1.90 (m, 1H). 10 [0301]

Reference Example 40

To a suspension of sodium hydride (0.52 g, 12 mmol) in DMF (15 mL) wasadded 6,7-dihydroxy-4-methyl-1,2-dihydroquinolin-2-one (0.50 g, 2.6mmol) at 0° C., and then the reaction mixture was stirred at the sametemperature for 30 minutes. Iodomethane (0.74 mL, 12 mmol) was added at0° C. thereto, and then the mixture was stirred at room temperature for18 hours. Saturated aqueous ammonium chloride was added to the reactionmixture at 0° C., and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, and thenconcentrated in vacuo. The obtained residue was purified by silica gelcolumn chromatography (chloroform:methanol=100:0-90:10) to give Compound(0-2) (0.47 g, 76% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.07 (s, 1H), 6.81 (s, 1H), 6.55 (s, 1H),4.02 (s, 3H), 3.96 (s, 3H), 3.73 (s, 3H), 2.45 (s, 3H).

Reference Example 41

To a solution of Compound (0-2) (0.47 g, 2.0 mmol) in DMF (15 mL) wasadded N-bromosuccinimide (0.36 g, 2.0 mmol), and then the reactionmixture was stirred at room temperature for 20 hours. Saturated aqueoussodium thiosulfate (10 mL) was added to the reaction mixture, and themixture was extracted with chloroform. The organic layer was washed withbrine, dried over sodium sulfate, and then concentrated in vacuo. Theresidue was dissolved in DMF (3 mL), water (20 mL) was added thereto,and the precipitated solid was collected by suction filtration to giveCompound (0-3) (0.53 g, 85% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.14 (s, 1H), 6.79 (s, 1H), 4.02 (s, 3H),3.97 (s, 3H), 3.81 (s, 3H), 2.68 (s, 3H).

Reference Example 42

According to the method described in Reference example 35, Compound(0-4) (0.58 g, 92% yield) was prepared from Compound (0-3) (0.53 g, 1.7mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.53 (s, 1H), 7.18 (s, 1H), 5.36 (s, 2H),5.28 (s, 2H), 3.77 (s, 3H), 3.56 (s, 3H), 3.56 (s, 3H), 2.65 (s, 3H).

Reference Example 43

According to the method described in Reference example 26, Compound(0-5) (0.24 g, 52% yield) was prepared from Compound (0-4) (0.25 g, 0.67mmol) and Compound (c-3) (0.43 g, 0.94 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.89 (brs, 1H), 7.53 (s, 1H), 7.26 (s, 1H),7.16 (s, 1H), 5.39-5.30 (m, 4H), 5.26 (s, 2H), 5.19 (dd, J=7.9, 5.5 Hz,2H), 4.56-4.34 (brm, 2H), 3.69 (s, 3H), 3.59 (s, 3H), 3.56 (s, 3H), 3.54(s, 3H), 3.52 (s, 3H), 2.31 (s, 3H), 1.10 (brs, 2H), 0.02 (s, 9H).

Reference Example 44

According to the method described in Reference example 28, Compound(0-6) (0.45 g) was prepared from Compound (0-5) (0.15 g, 0.21 mmol).

LC/MS (Condition (2)): [M+H]⁺/Rt=602/1.67 min

Reference Example 45

According to the method described in Reference example 29, Compound(0-7) (0.13 g, 61% yield) was prepared from Compound (0-6) (0.18 g) andCompound (d-4) (0.14 g, 0.30 mmol).

LC/MS (Condition (3)): [M+H]⁺/Rt=983/1.07 min

Example 15N-({4-[({[3-(6,7-Dihydroxy-1,4-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid

Compound (0-7) (0.13 g, 0.13 mmol) was dissolved in trifluoroacetic acid(2 mL), and then the reaction solution was stirred at room temperaturefor 2 hours. The reaction solution was concentrated by azeotropy withtoluene. The obtained residue was purified by reverse phasechromatography with an ODS column (0.05% aqueous trifluoroaceticacid/0.035% trifluoroacetic acid in acetonitrile) to give the titlecompound (46 mg, 51% yield).

LC/MS (Condition (2)): [M+H]⁺/Rt=694/1.27 min

¹H-NMR (CD₃OD, 400 MHz) δ: 8.60 (dd, J=7.8, 3.2 Hz, 1H), 8.07 (s, 1H),7.99 (s, 1H), 7.26 (s, 1H), 6.99 (s, 1H), 6.97 (s, 1H), 5.43 (s, 2H),5.18 (s, 2H), 4.48-4.43 (m, 1H), 3.68 (s, 3H), 2.39 (t, J=7.5 Hz, 2H),2.29 (s, 3H), 2.23-2.14 (m, 1H), 2.00-1.91 (m, 1H).

Reference Example 46

To 4,5-dimethoxy-pyridin-2-ylamine (0.15 g, 1.0 mmol) were addedpolyphosphoric acid (1.0 g) and ethyl acetoacetate (0.19 mL, 1.5 mmol).After stirring the reaction mixture at 100° C. for one hour, thereaction mixture was cooled to room temperature. The reaction mixturewas neutralized with aqueous sodium hydroxide, and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, and then concentrated in vacuo. The obtained crude product waswashed with ethyl acetate to give Compound (P-2) (0.10 g, 45% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=221/0.37 min

Reference Example 47

To a solution of Compound (P-2) (0.10 g, 0.45 mmol) in acetonitrile (2.5mL) was added N-iodosuccinimide (0.17 g, 0.75 mmol). After stirring thereaction mixture at 80° C. for 2 hours, the reaction mixture was cooledto room temperature. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over magnesium sulfate, and then concentrated invacuo. The obtained crude product was washed with hexane to giveCompound (P-3) (80 mg, 51% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=346/0.73 min

Reference Example 48

To a solution of Compound (P-3) (10 mg, 29 nmol) inN,N-dimethylformamide (1 mL) were added tripotassium phosphate (10 mg,47 nmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.2 mg, 15nmol), and tris(dibenzylideneacetone)dipalladium (6.9 mg, 7.5 nmol). Themixture was heated to 70° C., and a solution of Compound (a-2) (31 mg,45 nmol) in N,N-dimethylformamide (1 mL) was added thereto. Afterstirring the reaction mixture at 70° C. for one hour, a solution oftripotassium phosphate (10 mg, 47 nmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.2 mg, 15 nmol),tris(dibenzylideneacetone)dipalladium (6.9 mg, 7.5 nmol),tetrakis(triphenylphosphine)palladium (37 mg, 0.032 mmol), and Compound(a-2) (31 mg, 45 nmol) in N,N-dimethylformamide (1 mL) was addedthereto. After stirring the reaction mixture at 70° C. for one hour, thereaction mixture was cooled to room temperature. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnesium sulfate, andthen concentrated in vacuo. The obtained residue was purified by silicagel column chromatography (hexane:ethyl acetate=90:10-5:95) to giveCompound (P-4) (4.0 mg, 20% yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=625/1.02 min

Example 163-(7,8-Dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid

To a solution of Compound (P-4) (4.0 mg, 6.4 nmol) in chloroform (1 mL)was added boron tribromide (1 mol/L dichloromethane solution) (1 mL, 1mmol). After stirring the reaction mixture at 50° C. for one hour, borontribromide (1 mol/L dichloromethane solution) (1 mL, 1 mmol) was addedagain thereto. After stirring the reaction mixture at 50° C. for 8hours, the reaction mixture was cooled to room temperature. Methanol andtoluene were added to the reaction mixture, and water in the mixture wasremoved by azeotropy to obtain a dried residue. The obtained crudeproduct was washed with methanol to give the title compound (2.0 mg, 75%yield).

LC/MS (Condition (1)): [M+H]⁺/Rt=413/0.43 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.37 (brs, 1H), 9.43 (brs, 1H), 8.22 (s,1H), 8.20 (s, 1H), 6.96 (s, 1H), 6.54 (s, 1H), 2.20 (s, 3H).

Reference Example 49

To Compound (P-2) (0.98 g, 4.5 mmol) was added boron tribromide (1 mol/Ldichloromethane solution) (31 mL, 31 mmol), and then the reactionmixture was stirred under reflux for 12 hours. The reaction solution wascooled in ice bath, and methanol was added dropwise thereto. The mixturewas concentrated in vacuo. The procedure was repeated three times, andthe obtained residue was dried to give a crude product. To the obtainedcrude product was added dichloromethane (50 mL), and to the mixture inice bath were added N,N-diisopropylethylamine (11.4 mL, 66.7 mmol) andchloromethyl methyl ether (2.3 mL, 31 mmol). The obtained solution wasstirred at room temperature for one hour. To the reaction solution wasadded water, and the organic layer was washed. To the organic layer wasadded toluene, and the solution was concentrated in vacuo. The obtainedresidue was purified by amino-silica gel column chromatography(hexane/ethyl acetate 9:1-1:1) to give Compound (Q-1) (1.01 g, 81%yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.81 (s, 1H), 7.22 (s, 1H), 6.18 (s, 1H),5.40 (s, 2H), 5.31 (s, 2H), 3.55 (s, 3H), 3.54 (s, 3H), 2.41 (s, 3H).

Reference Example 50

According to the method described in Reference example 47, Compound(Q-2) (0.28 g, 86% yield) was prepared from Compound (Q-1) (0.23 g, 0.82mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.84 (s, 1H), 7.21 (s, 1H), 5.40 (s, 2H),5.30 (s, 2H), 3.54 (s, 6H), 2.70 (s, 3H).

Reference Example 51

Compound (Q-2) (0.20 g, 0.50 mmol), Compound (c-3) (0.28 g, 0.62 mmol),and bis(di-tert-butyl(4-dimethylamonophenyl)phosphine)dichloropalladium(35 mg, 0.05 mmol) were dissolved in THF (4 mL) under nitrogenatmosphere, and then 2 mol/L aqueous sodium carbonate (1 mL, 2.0 mmol)was added thereto. After stirring the reaction mixture at 65° C. for 3.5hours, saturated aqueous ammonium chloride was added to the reactionmixture, and the mixture was extracted with chloroform. The organiclayer was washed with brine, dried over sodium sulfate, and thenconcentrated in vacuo. The obtained residue was purified by silica gelcolumn chromatography (chloroform:ethyl acetate=25:75-0:100) to giveCompound (Q-3) (0.13 g, 37% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 8.79 (s, 1H), 7.95 (brs, 1H), 7.27 (s, 1H),7.27 (s, 1H), 7.20 (s, 1H), 5.42-5.38 (m, 2H), 5.35-5.31 (m, 2H),5.31-5.26 (m, 2H), 5.21-5.17 (m, 2H), 4.60-4.32 (brm, 2H), 3.60 (s, 3H),3.54 (s, 3H), 3.53 (s, 3H), 3.53 (s, 3H), 2.32 (s, 3H), 1.12-1.10 (brm,2H), 0.02 (s, 9H).

Reference Example 52

To a solution of Compound (Q-3) (0.13 g, 0.19 mmol) in THF (2 mL) wasadded tetrabutylammonium fluoride in THF (1 mol/L, 0.6 mL, 0.60 mmol),and then the reaction mixture was stirred at room temperature for onehour. After the reaction was terminated, the reaction solution wasconcentrated in vacuo to give Compound (Q-4) (0.38 g).

LC/MS (Condition (2)): [M+H]⁺/Rt=589/1.48 min

Example 17N-({4-[({[3-(7,8-Dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid

To a solution of Compound (Q-4) (0.38 g) in acetonitrile (2 mL) wasadded Compound (d-4) (0.20 g, 0.42 mmol), and then the reaction mixturewas stirred at room temperature for 21 hours. Saturated aqueous ammoniumchloride was added to the reaction mixture, and the mixture wasextracted with chloroform. The organic layer was washed with brine,dried over sodium sulfate, and then concentrated in vacuo. The obtainedresidue was purified by silica gel column chromatography(chloroform:methanol=97:3-90:10). The obtained crude product waspurified by reverse phase chromatography with an ODS column (0.05%aqueous trifluoroacetic acid/0.035% trifluoroacetic acid inacetonitrile) to give Compound (Q-5) (42.5 mg, 24% yield from CompoundQ-3).

Compound (Q-5) (42.5 mg, 0.044 mmol) was dissolved in trifluoroaceticacid (1.5 mL), and the solution was stirred at room temperature for 3hours. The reaction solution was concentrated in vacuo by azeotropy withtoluene. The obtained residue was washed with acetonitrile to give thetitle compound (19 mg, 64% yield from Compound Q-5).

LC/MS (Condition (2)): [M+H]⁺/Rt=681/1.20 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.54 (s, 1H), 9.68 (s, 1H), 8.79 (d, J=7.9Hz, 1H), 8.34 (s, 1H), 8.23-8.21 (m, 1H), 8.19 (s, 1H), 7.10 (s, 1H),6.50-6.44 (m, 1H), 5.25 (s, 2H), 4.37-4.31 (m, 2H), 2.43-2.37 (m, 2H),2.27 (s, 3H), 2.13-2.04 (m, 1H), 1.95-1.85 (m, 1H).

Example 18N-[({[3-(7,8-Dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamicacid

From Compound (Q-4) (0.14 g) and Compound (f-2) (94 mg, 0.25 mmol) whichwas prepared in a similar manner to Reference example 10, the titlecompound (20 mg, 20% yield from Compound Q-3) was prepared in a similarmanner to Example 17.

LC/MS (Condition (2)): [M+H]⁺/Rt=600/1.15 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.55-11.52 (brm, 1H), 9.97 (s, 1H),8.36-8.28 (m, 2H), 8.04 (s, 1H), 7.07 (d, J=1.2 Hz, 1H), 6.20 (brs, 1H),4.82 (dd, J=14.8, 7.0 Hz, 1H), 4.65 (d, J=14.8 Hz, 1H), 4.30-4.22 (m,1H), 2.20-2.10 (m, 2H), 2.15 (s, 3H), 1.93-1.84 (m, 1H), 1.78-1.68 (m,1H).

Reference Example 53

To a solution of Compound (E-2) (2.4 g, 3.5 mmol) in tetrahydrofuran (12mL) was added 1 mol/L tetrabutylammonium fluoride in tetrahydrofuran(9.1 mL, 9.1 mmol) dropwise, and then the reaction mixture was stirredat room temperature for one hour. Subsequently, 1 mol/Ltetrabutylammonium fluoride in tetrahydrofuran (1.4 mL) was addedthereto, and the reaction solution was stirred at room temperature forone hour. Furthermore, 1 mol/L tetrabutylammonium fluoride intetrahydrofuran (1.75 mL) was added thereto, and the reaction solutionwas stirred at room temperature for one hour. To the reaction solutionwas added toluene dropwise, and the mixture was cooled in ice bath. Theprecipitated solid was collected on a filter, and dried to give Compound(E-3′) (2.45 g, 84% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.03 (s, 1H), 8.82 (s, 1H), 8.16 (s, 1H),7.16 (s, 1H), 6.96 (s, 1H), 5.38 (s, 2H), 5.34 (s, 2H), 5.29 (s, 2H),5.26 (s, 2H), 3.81 (s, 3H), 3.65 (s, 3H), 3.56 (s, 3H), 3.53 (s, 3H),3.49 (s, 3H), 3.30-3.24 (m, 8H), 1.60-1.50 (m, 8H), 1.35-1.25 (m, 8H),0.87 (t, 12H, J=7.2 Hz).

Example 19N-[({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamicacid

From Compound (E-3′) (0.15 g, 0.18 mmol) and Compound (f-2) (0.10 mg,0.27 mmol) which was prepared in a similar manner to Reference example10, the title compound (67 mg, 63% yield) was prepared in a similarmanner to Example 17.

LC/MS (Condition (2)): [M+H]⁺/Rt=599/1.242 min

¹H-NMR (DMSO-de, 400 MHz) δ: 11.49 (br, 1H), 9.91 (s, 1H), 8.66-8.65 (m,1H), 8.37-8.33 (m, 1H), 8.24 (s, 1H), 7.58-7.56 (m, 1H), 7.06 (s, 1H),7.00 (s, 1H), 4.83-4.79 (m, 1H), 4.71-4.67 (m, 1H), 4.35-4.25 (m, 1H),3.81 (s, 3H), 2.18-2.11 (m, 2H), 2.15 (s, 3H), 1.97-1.87 (m, 1H),1.82-1.69 (m, 1H).

Reference Example 54

To a solution of ethylene glycol (5.0 mL) in THF (100 mL) was addedsodium hydride (0.19 g, 4.7 mmol) at 0° C., and then the reactionmixture was stirred warming to room temperature for 30 minutes. To thereaction mixture at 0° C. was added a solution of tert-butyl acrylate (2g, 16 mmol) in THF (50 mL) over 30 minutes, and the mixture was stirredat room temperature for 2 days, and concentrated in vacuo. The obtainedresidue was purified by silica gel column chromatography (pentane:ethylacetate=3:1-1:1) to give Compound (g-2) (0.34 g, 6.9% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 4.21-4.20 (m, 2H), 3.87-3.82 (m, 1H),3.75-3.70 (m, 2H), 3.59-3.56 (m, 2H), 2.52-2.49 (m, 2H), 1.46 (s, 9H).

Reference Example 55

To a solution of Compound (g-2) (0.15 g, 0.79 mmol) and triethylamine(0.16 g, 1.6 mmol) in THF (10 mL) was added methanesulfonyl chloride(0.13 g, 1.2 mmol) at 0° C., and then the reaction mixture was stirredat room temperature for 16 hours. The solvent was removed under reducedpressure, and the residue was dissolved in ethyl acetate (30 mL). Thesolution was washed with saturated aqueous sodium hydrogencarbonate,dried with sodium sulfate, and concentrated in vacuo to give Compound(g-3) (0.21 g, 100% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 3.68-3.64 (m, 4H), 3.03-2.99 (m, 2H), 2.98(s, 3H), 2.44-2.41 (m, 2H), 1.38 (s, 9H).

Reference Example 56

Compound (E-3′) (50 mg, 0.060 mmol), Compound (g-3) (81 mg, 0.30 mmol),and triethylamine (31 mg, 0.30 mmol) were dissolved in acetonitrile (2.5mL), and the solution was stirred at 45° C. for 24 hours. The solvent ofthe reaction solution was removed in vacuo, and the residue was purifiedby preparative TLC (methylene chloride:methanol=20:1) to give Compound(T-1) (32 mg, 70% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.30 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H),7.28 (s, 1H), 7.18 (s, 1H), 5.39 (s, 2H), 5.36 (s, 2H), 5.32 (s, 2H),5.19 (s, 2H), 4.63-4.55 (m, 2H), 3.85 (s, 3H), 3.83-3.75 (m, 2H),3.73-3.70 (m, 2H), 3.59-3.52 (m, 12H), 2.48-2.45 (m, 2H), 1.39 (s, 9H).15 [0323]

Example 203-[2-({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoicacid

To a solution of Compound (T-1) (32 mg, 0.040 mmol) in methylenechloride (3.0 mL) was added trifluoroacetic acid (2.0 mL) at 0° C., andthen the reaction mixture was stirred at room temperature for 10 hours.The solvent and trifluoroacetic acid were removed in vacuo, and then 2mol/L hydrogen chloride in methanol (10 ml) was added to the residue andthe solution was concentrated in vacuo to give the title compound (14mg, 59% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.55 (s, 1H), 8.27 (s, 1H), 7.59 (s, 1H),7.04-7.03 (m, 2H), 4.35-4.25 (m, 2H), 3.84 (s, 3H), 3.66-3.64 (m, 2H),3.61 (t, J=6.3 Hz, 2H), 2.42 (t, J=6.3 Hz, 2H).

Reference Example 57

To a solution of Compound (g-2) (0.20 g, 1.1 mmol) and triethylamine(0.31 g, 3.2 mmol) in THF (15 mL) was added p-toluenesulfonyl chloride(0.30 g, 1.6 mmol) at 0° C. over 10 minutes, and then the reactionmixture was stirred at at room temperature 16 hours. The solvent wasremoved in vacuo, and the residue was purified by preparative TLC(pentane:ethyl acetate=4:1) to give Compound (h-1) (0.20 g, 55% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.71 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2 Hz,2H), 4.07-4.05 (m, 2H), 3.55-3.54 (m, 4H), 2.39-2.33 (m, 5H), 1.36 (s,9H).

Reference Example 58

To a solution of Compound (h-1) (0.20 g, 0.57 mmol) in methylenechloride (30 mL) was added trifluoroacetic acid (0.28 g, 2.9 mmol) at 0°C., and then the reaction mixture was stirred at room temperature for 16hours. The solvent and trifluoroacetic acid were removed in vacuo, andthe residue was dried to give Compound (h-2) (0.17 g, 100% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.61 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz,2H), 4.09-4.07 (m, 2H), 3.64-3.59 (m, 4H), 2.37-2.35 (m, 2H), 2.30 (s,3H).

Reference Example 59

To a solution of Compound (h-2) (0.17 g, 0.57 mmol) in methylenechloride (5.0 mL) was added oxalyl chloride (0.22 g, 1.7 mmol) at 0° C.,and then the reaction mixture was stirred at room temperature for 6hours. The solvent and oxalyl chloride were removed in vacuo to give thecompound of formula (h-3) (0.17 g, 100% yield from h-2). To a solutionof di-tert-butyl L-glutamate hydrochloride (0.20 mg, 0.68 mmol) andtriethylamine (0.17 g, 1.7 mmol) in THF (20 mL) was added the compoundof formula (h-3) (0.17 g, 0.57 mmol) at 0° C., and the mixture wasstirred at room temperature for 30 minutes. The mixture was concentratedand purified by preparative TLC (pentane:ethyl acetate=3:1) to giveCompound (h-4) (0.24 g, h-3 yield from 62%).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.79-7.76 (m, 2H), 7.27-7.27 (m, 2H),6.51-6.49 (m, 1H), 4.43-4.37 (m, 1H), 4.12-4.10 (m, 2H), 3.63-3.57 (m,4H), 2.38-2.29 (m, 5H), 2.29-2.12 (m, 2H), 2.09-1.97 (m, 1H), 1.86-1.73(m, 1H), 1.39 (s, 9H), 1.36 (s, 9H). 20 [0327]

Reference Example 60

Compound (h-4) (0.30 g, 0.57 mmol), potassium bromide (0.20 g, 1.7mmol), and tetrabutylammonium bromide (91 mg, 0.28 mmol) were dissolvedin acetone (40 ml), and the reaction mixture was stirred at 80° C. for16 hours. The reaction mixture was cooled to room temperature, and theprecipitated solid was removed by filtration. The filtrate was dissolvedin ethyl acetate, and the solution was washed with water and dried oversodium sulfate. The solution was concentrated in vacuo to give Compound(h-5) (0.20 g, 79% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 4.52-4.48 (m, 1H), 3.82-3.75 (m, 2H),3.51-3.48 (m, 1H), 3.39-3.34 (m, 2H), 2.52-2.49 (m, 1H), 2.33-2.27 (m,2H), 2.17-2.09 (m, 1H), 1.94-1.85 (m, 1H), 1.71-1.65 (m, 3H), 1.46 (s,9H), 1.44 (s, 9H).

Reference Example 61

According to the method described in Reference example 56, Compound(U-1) (31 mg, 54% yield) was prepared from Compound (E-3′) (50 mg, 0.060mmol) and Compound (h-5) (0.12 g, 0.27 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.28 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H),7.28 (s, 1H), 7.18 (s, 1H), 6.71 (br, 1H), 5.39 (s, 2H), 5.35 (s, 2H),5.32 (s, 2H), 5.18 (s, 2H), 4.65-4.60 (m, 2H), 4.49-4.43 (m, 1H), 3.85(s, 3H), 3.88-3.83 (m, 2H), 3.80-3.74 (m, 2H), 3.60 (s, 3H), 3.56 (s,3H), 3.54 (s, 3H), 3.52 (s, 3H), 2.35-2.18 (m, 4H), 1.90-1.75 (m, 2H),1.46 (s, 9H), 1.41 (s, 9H).

Example 21N-{3-[2-({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethoxy]propanoyl}-L-glutamicacid

To a solution of Compound (U-1) (31 mg, 0.033 mmol) in methylenechloride (3.0 ml) was added trifluoroacetic acid (2.0 ml) at 0° C., andthe reaction mixture was stirred at room temperature for 10 hours. Thereaction mixture was concentrated in vacuo, and 4 M hydrogen chloride indioxane (1.0 ml) was added thereto. The mixture was stirred for 10minutes. The obtained residue was dissolved in DMF (3 ml), and diethylether (20 ml) was added thereto. The precipitated solid was collected togive the title compound (23 mg, 100% yield).

LC/MS (Condition (2)): [M+H]⁺/Rt=657/1.23 min

Reference Example 62

To a solution of 2-aminoethanol (0.20 g, 3.3 mmol) and potassiumhydrogen carbonate (1.6 g, 16 mmol) in DMF (10 ml) was added tert-butyl2-bromoacetate (3.0 g, 16 mmol) at 0° C., and the reaction mixture wasstirred at room temperature for 16 hours. The solvent of the reactionmixture was removed under reduced pressure, and then the residue waspurified by preparative HPLC to give Compound (i-2) (0.63 g, 34% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 3.54-3.51 (m, 2H), 3.44 (s, 4H), 2.89-2.87(m, 2H), 1.46 (s, 18H).

Reference Example 63

To a solution of Compound (i-2) (0.15 g, 0.52 mmol) and triethylamine(0.16 g, 1.6 mmol) in THF (10 mL) was added methanesulfonyl chloride(0.13 g, 1.2 mmol) at 0° C., and the reaction mixture was stirred atroom temperature for 16 hours. The solvent was removed under reducedpressure, and the residue was dissolved in ethyl acetate (30 mL). Thesolution was washed with saturated aqueous sodium hydrogencarbonate,dried over sodium sulfate, and concentrated in vacuo to give Compound(i-3) (0.21 g, 100% yield).

According to the method described in Reference example 56, Compound(V-1) (36 mg, 70% yield from E-3′) was obtained from Compound (E-3′) (50mg, 0.060 mmol) and Compound (i-3) (0.11 g, 0.30 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.39 (s, 1H), 8.84 (s, 1H), 8.17 (s, 1H),7.27 (s, 1H), 7.19 (s, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 5.31 (s, 2H),5.18 (s, 2H), 3.87 (s, 3H), 3.60-3.48 (m, 18H), 3.22-3.17 (m, 2H), 1.37(s, 18H).

Example 222,2′-{[2-({[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)ethyl]imino}-di-aceticacid

According to the method described in Example 21, the title compound (36mg, 100% yield) was prepared from Compound (V-1) (36 mg, 0.042 mmol).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.51 (s, 1H), 8.28 (s, 1H), 7.61 (s, 1H),7.09 (s, 1H), 7.08 (s, 1H), 4.11 (s, 4H), 3.89 (s, 3H), 3.51-3.49 (m,2H), 3.17-3.13 (m, 2H).

Reference Example 64

According to the method described in Reference example 55, Compound(j-2) (0.24 g, 100% yield) was prepared from(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.15 g, 1.1 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 4.41-4.35 (m, 1H), 4.23 (d, J=5.4 Hz, 2H),4.11 (dd, J=8.7, 6.6 Hz, 1H), 3.83 (dd, J=8.7, 5.4 Hz, 1H), 3.07 (s,3H), 1.44 (s, 3H), 1.36 (s, 3H).

Reference Example 65

According to the method described in Reference example 56, Compound(W-1) (31 mg, 73% yield) was prepared from Compound (E-3′) (50 mg, 0.060mmol) an Compound (j-2) (63 mg, 0.30 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.33 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H),7.29 (s, 1H), 7.19 (s, 1H), 5.39 (s, 2H), 5.36 (s, 2H), 5.32 (s, 2H),5.19 (s, 2H), 4.55-4.45 (m, 3H), 4.12-4.09 (m, 1H), 3.91-3.87 (m, 1H),3.85 (s, 3H), 3.59-3.52 (m, 12H), 1.43 (s, 3H), 1.34 (s, 3H). 5 [0335]

Example 23 2,3-Dihydroxypropyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate

To a solution of Compound (W-1) (31 mg, 0.040 mmol) in methanol (20 mL)was added 4 mol/L hydrogen chloride in methanol (0.50 mL) at 0° C., andthe reaction mixture was stirred at room temperature for 4 days. Thesolvent of the reaction mixture was removed under reduced pressure, andthe residue was purified by preparative HPLC to give the title compound(10 mg, 39% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.53 (s, 1H), 8.14 (s, 1H), 7.57 (s, 1H),6.95 (s, 1H), 6.82 (s, 1H), 4.27-4.24 (m, 1H), 4.12-4.07 (m, 1H), 3.76(s, 4H), 3.38-3.36 (m, 2H).

Reference Example 66

According to the method described in Reference example 55, Compound(k-2) (0.20 g, 100% yield) was prepared from tert-butyltrans-(4-hydroxymethylcyclohexyl)carbamate (0.15 g, 0.65 mmol).

According to the method described in Reference example 56, Compound(X-1) (36 mg, 75% yield from E-3′) was prepared from Compound (E-3′) (50mg, 0.060 mmol) and Compound (k-2) (92 mg, 0.30 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.22 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H),7.21 (s, 1H), 7.12 (s, 1H), 5.32 (s, 2H), 5.29 (s, 2H), 5.25 (s, 2H),5.10 (s, 2H), 4.32-4.13 (m, 4H), 3.79 (s, 3H), 3.51-3.45 (m, 12H),1.97-1.63 (m, 9H), 1.35 (s, 9H).

Example 24 (trans-4-Aminocyclohexyl)methyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylatehydrochloride

According to the method described in Example 23, the title compound (12mg, 49% yield) was prepared from Compound (X-1) (36 mg, 0.045 mmol).

¹H-NMR (MeOD, 400 MHz) δ: 8.30 (s, 1H), 8.04 (s, 1H), 7.65 (s, 1H), 7.06(s, 1H), 7.03 (s, 1H), 4.20 (s, 2H), 3.86 (s, 3H), 3.10-3.05 (m, 1H),2.05-2.02 (m, 2H), 1.94-1.91 (m, 2H), 1.79 (s, 1H), 1.43-1.34 (m, 2H),1.21-1.13 (m, 2H).

Reference Example 67

According to the method described in Reference example 55, Compound(I-2) (0.23 g, 100% yield) was prepared from(1,4-dimethylpiperazin-2-yl)methanol (0.15 g, 1.0 mmol).

According to the method described in Reference example 56, Compound(Y-1) (29 mg, 67% yield from E-3′) was prepared from Compound (E-3′) (50mg, 0.060 mmol) and Compound (I-2) (67 mg, 0.30 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.39-9.33 (m, 1H), 8.83-8.78 (m, 1H), 8.17(s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 5.39 (s, 2H), 5.35 (s, H), 5.32 (s,2H), 5.19 (s, 2H), 4.72-4.65 (m, 1H), 4.36-4.31 (m, 1H), 3.86 (s, 3H),3.59 (s, 3H), 3.56 (s, 3H), 3.54 (s, 3H), 3.52 (s, 3H), 2.87-2.84 (m,1H), 2.79-2.76 (m, 1H), 2.68-2.58 (m, 2H), 2.39 (s, 3H), 2.21 (s, 3H),2.09-1.98 (m, 1H), 1.49-1.42 (m, 1H), 1.34-1.28 (m, 1H). 10 [0339]

Example 25 (1,4-Dimethylpiperazin-2-yl)methyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylatehydrochloride

According to the method described in Example 23, the title compound (10mg, 40% yield) was prepared from Compound (Y-1) (29 mg, 0.040 mmol).

¹H-NMR (MeOD, 400 MHz) δ: 8.22 (s, 1H), 8.04 (s, 1H), 7.66 (s, 1H), 7.09(s, 1H), 6.79 (s, 1H), 3.90 (s, 3H), 3.25-3.21 (m, 2H), 3.16-3.12 (m,2H), 3.05-3.02 (m, 2H), 2.75-2.67 (m, 3H), 2.61 (s, 3H), 2.49 (s, 3H).

Example 26 (1-Methyl-1H-imidazol-2-yl)methyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylatehydrochloride

To a solution of Compound (E-3′) (80 mg, 0.096 mmol),(1-methyl-1H-imidazol-2-yl)methanol (m-1) (43 mg, 0.39 mmol), andtributylphosphine (59 mg, 0.29 mmol) in THF (6.0 ml) was addeddiisopropyl azodicarboxylate (59 mg, 0.29 mmol) at 0° C. Under argonatmosphere, the mixture was reacted at 50° C. under microwave for 5hours, and purified by preparative HPLC to give Compound (Z-1) (37 mg,56% yield). According to the method described in Example 21, the titlecompound (14 mg, 46% yield from Z-1) was obtained from Compound (Z-1).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.57 (s, 1H), 8.49 (s, 1H), 7.73 (s, 1H),7.70 (s, 1H), 7.68 (s, 1H), 7.28 (s, 1H), 7.11 (s, 1H), 4.08 (s, 3H),3.85 (s, 3H), 3.15 (s, 2H).

Reference Example 68

To 1-tert-butyl N-butoxycarbonyl-L-aspartate (0.20 g, 0.69 mmol) in1,2-dimethoxyethane (10 ml) were added 4-methylmorpholine (70 mg, 0.69mmol) and isobutyl chloroformate (94 mg, 0.69 mmol) at −15° C., and thereaction mixture was stirred for 10 minutes. The precipitation wasremoved by filtration and washed with cold 1,2-dimethoxyethane (20 ml).To the filtrate at −15° C. was added a solution of sodium borohydride(52 mg, 1.4 mmol) in water (5 ml). Five minutes later, water (250 ml)was added thereto. The mixture was extracted with ethyl acetate, and theorganic layer was dried over sodium sulfate, and concentrated in vacuoto give Compound (n-2) (0.17 g, 92% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 5.41-5.29 (m, 1H), 4.40-4.30 (m, 1H),3.73-3.58 (m, 2H), 3.45 (br, 1H), 3.01 (br, 1H), 2.18-2.06 (m, 1H), 1.48(s, 9H), 1.45 (s, 9H).

Reference Example 69

According to the method described in Reference example 55, Compound(n-3) (0.50 g, 100% yield) was prepared from Compound (n-2) (0.39 g, 1.4mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 5.13 (br, 1H), 4.25-4.19 (m, 3H), 2.96 (s,3H), 2.26-2.20 (m, 1H), 2.01-1.94 (m, 1H), 1.41 (s, 9H), 1.37 (s, 9H).

Reference Example 70

According to the method described in Reference example 56, Compound(AA-1) (34 mg, 67% yield) was prepared from Compound (E-3′) (50 mg,0.060 mmol) and Compound (n-3) (0.11 g, 0.30 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.44-9.22 (m, 1H), 8.98-8.78 (m, 1H), 8.17(s, 1H), 7.31 (s, 1H), 7.21 (s, 1H), 5.40-5.30 (m, 6H), 5.20 (br, 3H),3.96-3.91 (m, 2H), 3.88-3.84 (m, 1H), 3.59-3.52 (m, 12H), 3.48 (s, 3H),2.47-2.38 (m, 1H), 2.35-2.19 (m, 1H), 1.41 (s, 9H), 1.25 (s, 9H).

Example 27O-{[3-(6,7-Dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-homoserinehydrochloride

To a solution of Compound (AA-1) (34 mg, 0.040 mmol) in methanol (20 ml)was added 4 mol/L hydrogen chloride in dioxane (0.5 ml) at 0° C., andthe reaction mixture was stirred at room temperature for 4 days. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby preparative HPLC to give the title compound (10 mg, 41% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.39 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H),7.01 (s, 1H), 6.94 (s, 1H), 4.45-4.33 (m, 2H), 3.80 (s, 3H), 3.54-3.46(m, 1H), 2.35-2.21 (m, 1H), 2.11-1.99 (m, 1H).

Reference Example 71

According to the method described in Reference example 56, Compound(BA-1) (47 mg, 85% yield) was prepared from Compound (E-3′) (50 mg,0.060 mmol) and 1,2-dibromoethane (72 mg, 0.39 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.30 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H),7.30 (s, 1H), 7.18 (s, 1H), 5.39 (s, 2H), 5.36 (s, 2H), 5.30 (s, 2H),5.20 (s, 2H), 4.86-4.64 (m, 2H), 3.85 (s, 3H), 3.73-3.72 (m, 2H), 3.59(s, 3H), 3.56 (s, 3H), 3.54 (s, 3H), 3.53 (s, 3H).

Example 28 2-(3-Hydroxypyrrolidin-1-yl)ethyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate

Compound (BA-1) (47 mg, 0.068 mmol),3-(tetrahydropyran-2-yloxy)-pyrrolidine (58 mg, 0.34 mmol), andtriethylamine (34 mg, 0.34 mmol) were dissolved in acetonitrile (5.0ml), and the reaction mixture was stirred at 35° C. for 16 hours. Thereaction mixture was concentrated in vacuo, and the residue was purifiedby preparative TLC (methylene chloride:methanol=20:1) to give Compound(BA-2) (51 mg, 96% yield from BA-1).

To solution of Compound (BA-2) in methanol (15 ml) was added 4 mol/Lhydrochloric acid in dioxane (0.16 ml, 0.65 mmol) at 0° C., and thereaction mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated in vacuo to give the title compound(13 mg, 36% yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.47 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H),7.11 (s, 1H), 7.03 (m, 1H), 4.43-4.39 (m, 3H), 3.83 (s, 3H), 3.33-3.27(m, 2H), 3.14-3.04 (m, 4H), 1.87-1.78 (m, 2H).

Reference Example 72

To a solution of 3,6,9,12-tetraoxatetradecan-1,14-diol (0.50 g, 2.1mmol), potassium iodide (69 mg, 0.42 mmol), and silver oxide (48 mg,0.21 mmol) in methylene chloride (50 ml) was added p-toluenesulfonylchloride (0.36 g, 1.9 mmol) at 0° C., and the reaction mixture wasstirred at room temperature for 16 hours. The reaction mixture waspurified by preparative TLC (methylene chloride:methanol=10:1) to giveCompound (p-2) (0.31 g, 38% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 7.80 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz,2H), 4.17-4.15 (m, 2H), 3.71-3.60 (m, 19H), 2.45 (s, 3H).

Reference Example 73

A solution of Compound (p-2) (0.13 g, 0.32 mmol), potassium bromide(0.11 g, 0.95 mmol), and tetrabutylammonium bromide (0.10 g, 0.32 mmol)in acetone (10 ml) was stirred at 80° C. for 10 hours. The solvent wasremoved under reduced pressure, and the residue was purified by silicagel column chromatography (methylene chloride:methanol=20:1) to giveCompound (p-3) (83 mg, 87% yield).

¹H-NMR (CDCl₃, 400 MHz) δ: 3.83-3.79 (m, 2H), 3.74-3.70 (m, 2H),3.70-3.62 (m, 8H), 3.62-3.61 (m, 2H), 3.49-3.46 (m, 2H), 2.96 (br, 1H),1.75 (s, 4H).

Reference Example 74

According to the method described in Reference example 56, the titlecompound (CA-1) (34 mg, 70% yield) was prepared from Compound (E-3′) (50mg, 0.060 mmol) and Compound (p-3) (91 mg, 0.30 mmol).

¹H-NMR (CDCl₃, 400 MHz) δ: 9.20 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H),7.21 (s, 1H), 7.12 (s, 1H), 5.33 (s, 2H), 5.29 (s, 2H), 5.25 (s, 2H),5.12 (s, 2H), 3.79 (s, 3H), 3.62-3.58 (m, 6H), 3.52-3.49 (m, 20H), 3.47(s, 3H), 3.45 (s, 3H).

Example 29 14-Hydroxy-3,6,9,12-tetraoxatetradec-1-yl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate

According to the method described in Example 23, the title compound (12mg, 45% yield) was prepared from Compound (CA-1) (34 mg, 0.042 mmol).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.58 (s, 1H), 8.16 (s, 1H), 7.57 (s, 1H),7.01 (s, 1H), 6.95 (s, 1H), 4.31 (br, 2H), 3.77 (s, 3H), 3.68 (br, 2H),3.51-3.36 (m, 16H). 10 [0351]

Example 30 2-Amino-2-oxoethyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate

According to the method described in Reference example 56, Compound(DA-1) (31 mg, 80% yield) was prepared from Compound (E-3′) (50 mg,0.060 mmol) and 2-bromoacetamide (41 mg, 0.30 mmol).

According to the method described in Example 27, the title compound (22mg, 92% yield) was prepared from Compound (DA-1) (31 mg, 1.8 mmol).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.49 (s, 1H), 8.18-8.11 (m, 1H), 7.58 (s,1H), 7.01 (s, 1H), 6.90 (s, 1H), 4.59-4.76 (m, 2H), 3.79 (s, 3H).

Example 31 2-(3-Methoxy-3-oxopropoxy)ethyl3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylate

To a solution of Compound (T-1) (32 mg, 0.040 mmol) in methanol (20 ml)was added 4 mol/L hydrogen chloride in dioxane (0.5 ml, 2.0 mmol) at 0°C., and the reaction mixture was stirred at room temperature for 4 days.The reaction mixture was concentrated in vacuo and the residue waspurified with a preparative HPLC to give the title compound (10 mg, 42%yield).

¹H-NMR (DMSO-de, 400 MHz) δ: 8.40 (s, 1H), 8.10 (s, 1H), 7.58 (s, 1H),7.01 (s, 1H), 6.84 (s, 1H), 4.31-4.26 (m, 2H), 3.79 (s, 3H), 3.70-3.59(m, 4H), 3.52 (s, 4H), 2.51-2.49 (m, 2H).

(Test 1) Inhibitory Activity for the Collapse Activity Caused by Sema3A

96 well-plate (SUMITOMO BAKELITE CO., LTD.) which was beforehand coatedwith polylysine was further coated with laminin (10 μL laminin, at roomtemperature, for 1 hour). To each well was added 100 μL of a medium (F12medium containing 10% fetal bovine serum, 20 ng/mL NGF, 100 unit/mLpenicillin, and 100 μg/mL streptomycin). Dorsal root ganglion harvestedfrom 7-8 day-old chick embryo was inoculated thereto, and the culturemedium was cultivated under the condition of 5% CO₂ and 37° C. for 16-20hours. And then, each test compound in various concentrations was addedto the medium, each test medium was cultivated for 30 minutes, 3units/mL mouse semaphorin 3A (Sema3A) was added to each medium, and theneach test medium was cultivated for more 30 minutes. Then,glutaraldehyde was added to the medium, in which the final concentrationof glutaraldehyde was 1%. The medium was left to stand at roomtemperature for 15 minutes to make the tissue fragment fixed, and theratio of the retracted growth cone was measured under a microscope. Thefollowing Table 1 shows the result of the collapse assay about eachconcentration of each compound in Test 1, i.e., residual ratio (%) ofSema3A activity. It means that the smaller the value is, the more potentthe Sema3A inhibitory activity is. According to the result of theassessment, it has been found that all of the compound group shown inTable 1 have strong Sema3A inhibitory activity.

TABLE 1 Example 1 μM 3 μM 10 μM  1 2.0 4.6 —  3 4.0 — —  4 6.0 — —  55.1 3.3 —  7 — <70 <40  8 27.3 21.0 —  9 3.4 7.3 — 11 7.9 — — 12 65.5 —— 13 — — <70 14 78.8 6.1 — 15 5.4 0.0 — 16 15.9 2.2 — 17 90.1 3.3 — 1821.8 6.7 — 19 4.2 0.0 — 23 <70 <10 — 24 <70 <10 — 27 <10 <10 — 30 — <40— —: untested

(Test 2) Inhibitory Activity for the Neuropilin-Binding Activity Causedby Sema3A

To each well of 96 well-plate (IWAKI) was seeded CHO cellsstably-expressing mouse neuropilin, the cells were cultivated in F12medium (10% fetal bovine serum, 100 units/mL penicillin, and 100 μg/mLstreptomycin) under the condition of 5% CO₂ and 37° C. for 18 hours. Andthen, the culture medium was removed, and mouse Sema3A which includedeach test compound and alkaline phosphatase (AP) in variousconcentrations was added thereto, and the culture was reacted at roomtemperature for more one hour. Then, the reaction solution was removed,the residual cells were washed with HBSS solution (0.25% BSA) anddissolved in a solution (10 mM Tris including 1% Triton X-100) at 65° C.for one hour, and the AP activity thereof was measured. The followingtable 2 (Test 2) shows the result of inhibitory activity of eachcompound, i.e., residual ratio (%) of avidity. It means that the smallerthe value is, the more potent the binding inhibitory activity. Accordingto the result of the assessment, it has been found that all of thecompound group shown in Table 2 have binding inhibitory activity forSema3A.

TABLE 2 Example 100 μM 20 56.5 21 58.5 22 62.1 25 90.5 26  97.8* 28 87.129 49.3 31 69.4 —: untested *it is the result when the concentration ofthe test compound is 10 μM.

(Test 3) Drug Evaluation for Corneal Disorder in Dry Eye-Model Rat

A model rat whose exorbital lacrimal gland is excised is generally usedas a model for evaluating the drug efficacy for corneal disorder causedby dry eye. As for corneal disorder of the rat, hyaluronic acid (HA) anddiquafosol sodium (DQS) which are existing drugs, and the presentcompound (Example 3) were administered to the rat, and each efficacythereof was evaluated.

Male SD rat was anesthetized with inhalational isoflurane, and theexorbital lacrimal gland thereof was excised to prepare a dry eye-modelrat (the conditions to prepare the dry eye-model rat can be changed asnecessary, for example, by combining the excision of exorbital lacrimalgland with the medication of streptozotocin or the like). Three weeksafter the operation, each vehicle for eye drop (typicallyphosphate-buffered saline (PBS)), 0.3% HA ophthalmic solution, 3% DQSophthalmic solution, and the ophthalmic solution of the present compound(Example 3) were administered to the rat in an awareness at 1 μL pershot, 6 times per day, for 4 weeks.

The site of corneal disorder was stained with a fluorescein (FITC)solution, and the extent of the disorder was evaluated with the scoregained from the following method. First, the rat was anesthetized withinhalational isoflurane, and 1 μL of 0.5% FITC solution was dropped intothe cornea of the rat. The extra FITC solution was washed with salinecompletely, and the site of corneal disorder was stained. Next, thestaining of FITC in the rat's cornea was observed with a portable slitlamp, and evaluated with the following scores of 0-3 (Atarashii Ganka(Journal of the Eye); 21: 87-90(2004)).

(Evaluation Criteria)

0: no punctate stain (normal)

1: sparse punctate stain (punctate fluorescein-strains exist away eachother)

2: middle (middle between 1 and 3)

3: dense punctate stain (punctate fluorescein strains exist closely eachother)

The statistical significance for the drug effect was evaluated bynonparametric Tukey's multiple comparison test, in which the result ofeach test group was compared with that of the control (intact) groupwhich was not operated by excising exorbital lacrimal gland.

The HA ophthalmic solution and the DQS ophthalmic solution exhibitedonly a little bit of the therapeutic effect for corneal disorder causedby dry eye. On the other hand, the compound of Example 3 exhibited apotent therapeutic effect for the corneal disorder, which suggests thatthe compound can normalize corneal disorder caused by dry eye. In asimilar way, compared with the vehicle-administration group (PBS) inwhich the rat's exorbital lacrimal gland is excised, the compound ofExample 3 exhibited a significant improvement (** denotes p<0.01), butneither the HA ophthalmic solution nor the DQS ophthalmic solutionexhibited any significant improvement.

(Test 4) Drug Evaluation for the Dysfunction of Corneal Nerves in DryEye Rat Model

Male SD rat was anesthetized with inhalational isoflurane. The exorbitallacrimal gland thereof was excised, and at the same day, streptozotocinwas administered intraperitoneally to the rat (55 mg/kg) to prepare adry eye-model rat associated with the dysfunction of corneal nerves.Several weeks after the operation, 0.3% HA ophthalmic solution, 3% DQSophthalmic solution, and 0.1% the ophthalmic solution of the presentcompound (Example 3) were administered to the rat in an awareness at 1μL per shot, 6 times per day, for 4 weeks.

The cornea of the rat was softly held by hand. The drug effect for thedysfunction of corneal nerves was evaluated through blink reflex bycontacting the cornea with the nylon filament of cochet-bonnet cornealesthesiometer. First, the tip of the nylon filament (length: 60 mm,diameter: 0.12 mm) was made to almost-vertically contact with the centerof cornea, and the nylon filament was made to curve a little. And then,the experiment was continued while the nylon filament was shortenedgradually, and the length of nylon string which the blink reflex of therat was observed was identified as corneal perception (Invest OphthalmolVis Sci.; 53: 8067-74 (2012)).

The statistical significance for the drug effect was evaluated byconfirming that P value is less than 5% in Student's t test between theintact group and the PBS group, and then carrying out Student's t testbetween the intact group and the present compound group. Lastly,Student's t tests between the intact group and the HA group, and betweenthe intact group and the DQS group were carried out for the purpose ofreference.

The HA ophthalmic solution and the DQS ophthalmic solution did notexhibit any therapeutic effect for the dysfunction of corneal nervescaused by dry eye at all. On the other hand, the compound of Example 3exhibited a marked therapeutic effect for the dysfunction of cornealnerves, which suggests that the compound can normalize the dysfunctionof nerves as clinical condition.

(Test 5) Drug Evaluation for Corneal Disorder in Dry Eye Rat Model

For the corneal disorder in the model rat whose exorbital lacrimal glandis excised, the drug effect was evaluated about hyaluronic acid (HA)which is an existing drug, and the present compound.

Male SD rat was anesthetized with inhalational isoflurane, and theexorbital lacrimal gland thereof was excised to prepare a dry eye-modelrat (the conditions to prepare the dry eye-model rat can be changed asnecessary, for example, by combining the excision of exorbital lacrimalgland with the medication of streptozotocin or the like). Three weeksafter the operation, each vehicle for eye drop (typicallyphosphate-buffered saline (PBS)), and 0.01%, 0.1%, and 1% the ophthalmicsolutions of the present compound (Example 19) were administered to therat in an awareness at 1 μL per shot, twice per day, for 4 weeks.

The scoring of disorder extent in the site of corneal disorder wasevaluated with 4 grades of the evaluation criteria of 0-3 according toTest 3.

The statistical significance for the drug effect was evaluated bynonparametric Tukey's multiple comparison test, in which the result ofeach test group was compared with that of the vehicle-administrationgroup (PBS) in which the rat's exorbital lacrimal gland is excised.

The compound of Example 19 (in the concentration of 0.01% to 1%)exhibited a marked improvement (** denotes p<0.01) for corneal disorder,which suggests that the compound can normalize corneal disorder causedby dry eye.

INDUSTRIAL APPLICABILITY

The compound of formula (1) or a pharmaceutically acceptable saltthereof of the present invention has a semaphorin inhibitory activity,and it is useful as a nerve regeneration promoter in peripheral orcentral nerve, or a medicament for treating or preventing neuropathicdisease/neurodegenerative disease, a neurological disease associatedwith ischemic damage, and corneal disease, which includes the nerveregeneration promoter.

1-28. (canceled)
 29. A method of preparing a compound of Formula (1B):

wherein R¹-L- is R¹—OC(O)— or R¹—NHC(O)—; and R¹ is (i) hydrogen atom,(ii) optionally-substituted C₁₋₆ alkyl group, (iii)optionally-substituted C₂₋₆ alkenyl group, (iv) optionally-substitutedC₂₋₆ alkynyl group, (v) optionally-substituted 3- to 8-memberedcycloalkyl group, (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, (viii) optionally-substituted 5-to 10-membered unsaturated aliphatic heterocyclyl group, (ix)optionally-substituted 6- to 10-membered aryl group, or (x)optionally-substituted 5- to 10-membered heteroaryl group, wherein thesubstituent(s) of the (ii) optionally-substituted C₁₋₆ alkyl group isone or more substituents selected independently from the groupconsisting of hydroxy group, methoxy group, ethoxy group, carboxylgroup, carbamoyl group (which may be substituted with one or two thesame or different C₁₋₃ alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ areindependently hydrogen atom, C₁₋₃ alkyl group, carboxylmethyl group,2-hydroxy ethyl group, or 2-aminoethyl group), optionally-substituted 3-to 6-membered cycloalkyl group (wherein the substituent(s) of saidoptionally-substituted 3- to 6-membered cycloalkyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group),optionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup (wherein the substituent(s) of said optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), andoptionally-substituted 5- to 10-membered heteroaryl group (wherein thesubstituent(s) of said optionally-substituted 5- to 10-memberedheteroaryl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), or the (ii) optionally-substituted C₁₋₆ alkyl groupmay be any one of the following groups of formulae (4)-(6): formula (4):

wherein m is 1, 2, 3, 4, or 5, R⁷ is C₁₋₃ alkoxy group, amino acid group(which binds to C(O) at its N terminus), and peptide consisting of 2-3amino acid residues (which binds to C(O) at its N terminus), formula(5):R⁸-L²-(CH₂CH₂O)_(q)CH₂CH₂

  (5) wherein q is 1, 2, 3, 4, or 5, L² is single bond or C(O), R⁸ ishydroxy group, C₁₋₃ alkoxy group, amino group which may be substitutedwith one or two the same or different C₁₋₃ alkyl, amino acid group(which binds to L² at its N terminus), or peptide consisting of 2-3amino acid residues (which binds to L² at its N terminus), formula (6):

wherein L³ is CH₂ or C(O), and R⁹ is hydroxy group, C₁₋₃ alkoxy group,amino group which may be substituted with one or two the same ordifferent C₁₋₃ alkyl, amino acid group (which binds to L³ at its Nterminus), or peptide consisting of 2-3 amino acid residues (which bindsto L³ at its N terminus), the substituent(s) of the (iii)optionally-substituted C₂₋₆ alkenyl group, and the (iv)optionally-substituted C₂₋₆ alkynyl group are independently one or moresubstituents selected independently from the group consisting of hydroxygroup, methoxy group, ethoxy group, carboxyl group, carbamoyl group(which may be substituted with one or two the same or different C₁₋₃alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ are independently hydrogen atom, C₁₋₃alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethylgroup), optionally-substituted 3- to 6-membered cycloalkyl group(wherein the substituent(s) of said optionally-substituted 3- to6-membered cycloalkyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, hydroxygroup, and carboxyl group), optionally-substituted 4- to 6-memberedsaturated aliphatic heterocyclyl group (wherein the substituent(s) ofsaid optionally-substituted 4- to 6-membered saturated aliphaticheterocyclyl group is one or more substituents selected independentlyfrom the group consisting of amino group which may be substituted withone or two the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxygroup, and carboxyl group), and 5- to 10-membered heteroaryl group, thesubstituent(s) of the (v) optionally-substituted 3- to 8-memberedcycloalkyl group, the (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, the (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, the (viii)optionally-substituted 5- to 10-membered unsaturated aliphaticheterocyclyl group, the (ix) optionally-substituted 6- to 10-memberedaryl group, and the (x) optionally-substituted 5- to 10-memberedheteroaryl group are independently one or more substituents selectedindependently from the group consisting of hydroxy group, methoxy group,ethoxy group, amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, and carboxyl group; R² is hydrogen atom,hydroxy group, or carboxyl group; R³ is (i) hydrogen atom, (ii)optionally-substituted C₁₋₆ alkyl group, (iii) optionally-substitutedC₂₋₆ alkenyl group, (iv) optionally-substituted C₂₋₆ alkynyl group, (v)optionally-substituted 3- to 8-membered cycloalkyl group, (vi)optionally-substituted 4- to 8-membered cycloalkenyl group, (vii)optionally-substituted 4- to 8-membered saturated aliphatic heterocyclylgroup, (viii) optionally-substituted 5- to 10-membered unsaturatedaliphatic heterocyclyl group, (ix) optionally-substituted 6- to10-membered aryl group, or (x) optionally-substituted 5- to 10-memberedheteroaryl group; and X

Y

Z is X═Y—Z, X—Y═Z, or X—Y—Z, X is nitrogen atom, or NR⁴, R⁴ is (i)hydrogen atom, (ii) optionally-substituted C₁₋₆ alkyl group, (iii)optionally-substituted C₂₋₆ alkenyl group, (iv) optionally-substitutedC₂₋₆ alkynyl group, (v) optionally-substituted 3- to 8-memberedcycloalkyl group, (vi) optionally-substituted 4- to 8-memberedcycloalkenyl group, (vii) optionally-substituted 4- to 8-memberedsaturated aliphatic heterocyclyl group, (viii) optionally-substituted 5-to 10-membered unsaturated aliphatic heterocyclyl group, (ix)optionally-substituted 6- to 10-membered aryl group, or (x)optionally-substituted 5- to 10-membered heteroaryl group, Y is carbonatom or CH, and Z is carbon atom, CH, or nitrogen atom, provided thatthe combination of X, Y, and Z should be any one of chemically-possibleselections or a pharmaceutically acceptable salt thereof; whichcomprises the following step: (step A1) reacting the compound of Formula(1A):

wherein R², R³, X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof in the presence of a halogenating agent, followed byreacting with R¹NH₂ or R¹OH to give a compound of formula (1B).
 30. Themethod of claim 29, wherein the method further comprises the followingsteps B1 and B2 preparing for the compound of Formula (1A):

wherein R², R³, X

Y

Z, X, Y and Z are as defined in claim 29, or a pharmaceuticallyacceptable salt thereof; before the step A1: (step B1) coupling thecompound of Formula (1a):

wherein R¹¹ and R¹² are independently a protecting group of hydroxygroup; R¹³ is a protecting group of carboxyl group; and R¹⁴ is afunctional group selected from the group consisting of tributyltingroup, pinacolboryl group, and hydroxyboryl group, or a pharmaceuticallyacceptable salt thereof; and a compound of Formula (1b):

wherein R³, X

Y

Z, X, Y and Z are as defined above; R¹⁵ and R¹⁶ are independently aprotecting group of hydroxy group; R¹⁷ is hydrogen atom, a protectedhydroxy group, or a protected carboxyl group; and R¹⁸ is a halogen atom,or a pharmaceutically acceptable salt thereof in the presence of a base,a phosphine ligand, a copper catalyst and a palladium catalyst to give acompound of Formula (1c):

wherein R³, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R¹⁷, X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof; and (step B2) removing the protecting groups from thecompound of formula (1c) to obtain a compound of the formula (1A), or apharmaceutically acceptable salt thereof.
 31. The method of claim 29,wherein R¹ is (i) hydrogen atom, or (ii) optionally-substituted C₁₋₃alkyl group, wherein the substituent(s) of the (ii)optionally-substituted C₁₋₃ alkyl group is one or more substituentsselected independently from the group consisting of hydroxy group,methoxy group, ethoxy group, carboxyl group, carbamoyl group (which maybe substituted with one or two the same or different C₁₋₃ alkyl), NR⁵R⁶(wherein R⁵ and R⁶ are independently hydrogen atom, C₁₋₃ alkyl group,carboxylmethyl group, 2-hydroxy ethyl group, or 2-aminoethyl group),optionally-substituted 3- to 6-membered cycloalkyl group (wherein thesubstituent(s) of said optionally-substituted 3- to 6-memberedcycloalkyl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group (wherein the substituent(s) of saidoptionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup is one or more substituents selected independently from the groupconsisting of amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, andcarboxyl group), and optionally-substituted 5- to 10-membered heteroarylgroup (wherein the substituent(s) of said optionally-substituted 5- to10-membered heteroaryl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), or the (ii)optionally-substituted C₁₋₃ alkyl group may be any one of the groups offormulae (4)-(6), in formula (4), m is 1, R⁷ is amino acid group (whichbinds to C(O) at its N terminus), in formula (5), q is 1, 2, 3, 4, or 5,L² is single bond or C(O), R⁸ is hydroxy group or amino acid group(which binds to L² at its N terminus), in formula (6), L³ is C(O), R⁹ ishydroxy group or amino acid group (which binds to L³ at its N terminus).32. A method of preparing a compound of Formula (1Ba):

wherein R¹, R², R³, X

Y

Z, X, Y and Z are as defined in claim 29, or a pharmaceuticallyacceptable salt thereof; which comprises the following steps C1 to C3:(step C1) removing R¹³ which is among the protecting groups from thecompound of formula (1c):

wherein R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R¹⁷ are as defined in claim 30; and R³,X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof; to obtain a compound of the formula (1d):

wherein, R³, R¹¹, R¹², R¹⁵, R¹⁶, R¹⁷, X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof; (step C2) reacting the compound of Formula (1d) withR⁰-LG: wherein R⁰ is R¹ or a protected R¹; R¹ is as defined above; andLG is a leaving group in the presence of a base to give a compound ofFormula (1e):

wherein R⁰ is as defined above; and R³, R¹¹, R¹², R¹⁵, R¹⁶, R¹⁷, X

Y

Z, X, Y and Z are as defined in claim 29 or a pharmaceuticallyacceptable salt thereof; and (step C3) removing R¹¹, R¹², R¹⁵, R¹⁶ andthe protecting groups of R⁰ and R¹⁷ from the compound of formula (1e) togive a compound of Formula (1Ba) or a pharmaceutically acceptable saltthereof.
 33. The method of claim 32, wherein R¹ is (i) hydrogen atom, or(ii) optionally-substituted C₁₋₃ alkyl group, wherein the substituent(s)of the (ii) optionally-substituted C₁₋₃ alkyl group is one or moresubstituents selected independently from the group consisting of hydroxygroup, methoxy group, ethoxy group, carboxyl group, carbamoyl group(which may be substituted with one or two the same or different C₁₋₃alkyl), NR⁵R⁶ (wherein R⁵ and R⁶ are independently hydrogen atom, C₁₋₃alkyl group, carboxylmethyl group, 2-hydroxy ethyl group, or2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkylgroup (wherein the substituent(s) of said optionally-substituted 3- to6-membered cycloalkyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), optionally-substituted 4- to6-membered saturated aliphatic heterocyclyl group (wherein thesubstituent(s) of said optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), and optionally-substituted 5-to 10-membered heteroaryl group (wherein the substituent(s) of saidoptionally-substituted 5- to 10-membered heteroaryl group is one or moresubstituents selected independently from the group consisting of aminogroup which may be substituted with one or two the same or differentC₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, and carboxyl group), or the(ii) optionally-substituted C₁₋₃ alkyl group may be any one of thegroups of formulae (4)-(6), in formula (4), m is 1, R⁷ is amino acidgroup (which binds to C(O) at its N terminus), in formula (5), q is 1,2, 3, 4, or 5, L² is single bond or C(O), R⁸ is hydroxy group or aminoacid group (which binds to L² at its N terminus), in formula (6), L³ isC(O), R⁹ is hydroxy group or amino acid group (which binds to L³ at itsN terminus).
 34. A method of preparing a compound of Formula (1Bd):

wherein R², R³, L, R⁹, L³, X

Y

Z, X, Y and Z are as defined in claim 29, or a pharmaceuticallyacceptable salt thereof; which comprises the following step: (step D1)reacting a compound of Formula (1Bc):

wherein R², R³, X

Y

Z, X, Y, Z and L are as defined above, or a pharmaceutically acceptablesalt thereof; with the compound of formula (1f):

wherein R¹⁹ is a protected R⁹; and R⁹ and L³ is as defined above in thepresence of a reducing agent,tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, and a coppercatalyst, followed by removing the protecting group to give the compoundof formula (1Bd) or a pharmaceutically acceptable salt thereof, whereinthe step D1 may be replaced with the following step D2: (step D2)reacting the compound of Formula (1Bc) with the compound of Formula(1j):

wherein R⁹ is as defined above, or a salt thereof, in the presence of areducing agent, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, and acopper catalyst to give the compound of formula (1Bd) or apharmaceutically acceptable salt thereof.
 35. A method of preparing thecompound of Formula (1D):

wherein R¹, R², R³, L, X

Y

Z, X, Y and Z are as defined in claim 29, or a pharmaceuticallyacceptable salt thereof; which comprises the following step: (step E1)reacting the compound of Formula (1C):

wherein R², R³, X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof, with a halogenating agent, followed by reacting with analcohol compound or an amine compound which corresponds to a desired R¹to give the compound of formula (1D).
 36. The method of claim 35,wherein the method further comprises the following steps F1 and F2preparing the compound of Formula (1C):

wherein R², R³, X

Y

Z, X, Y and Z are as defined in claim 29, or a pharmaceuticallyacceptable salt thereof; before the step E1: (step F1) coupling thecompound of Formula (1a):

wherein R¹¹, R¹², R¹³ and R¹⁴ are as defined in claim 30, or apharmaceutically acceptable salt thereof; and a compound of Formula(1r):

wherein R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are as defined in claim 30; and R³, X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof in the presence of a base, a phosphine ligand, a coppercatalyst and a palladium catalyst to give a compound of Formula (1s):

wherein R³, R¹¹, R¹², R¹³, R¹⁵, R¹⁶, R¹⁷, X

Y

Z, X, Y and Z are as defined above, or a pharmaceutically acceptablesalt thereof; and (step F2) removing the protecting groups from thecompound of formula (1s) to obtain a compound of the formula (1C), or apharmaceutically acceptable salt thereof.
 37. The method of claim 35,wherein R¹ is (i) hydrogen atom, or (ii) optionally-substituted C₁₋₃alkyl group, wherein the substituent(s) of the (ii)optionally-substituted C₁₋₃ alkyl group is one or more substituentsselected independently from the group consisting of hydroxy group,methoxy group, ethoxy group, carboxyl group, carbamoyl group (which maybe substituted with one or two the same or different C₁₋₃ alkyl), NR⁵R⁶(wherein R⁵ and R⁶ are independently hydrogen atom, C₁₋₃ alkyl group,carboxylmethyl group, 2-hydroxy ethyl group, or 2-aminoethyl group),optionally-substituted 3- to 6-membered cycloalkyl group (wherein thesubstituent(s) of said optionally-substituted 3- to 6-memberedcycloalkyl group is one or more substituents selected independently fromthe group consisting of amino group which may be substituted with one ortwo the same or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group,and carboxyl group), optionally-substituted 4- to 6-membered saturatedaliphatic heterocyclyl group (wherein the substituent(s) of saidoptionally-substituted 4- to 6-membered saturated aliphatic heterocyclylgroup is one or more substituents selected independently from the groupconsisting of amino group which may be substituted with one or two thesame or different C₁₋₃ alkyl, C₁₋₃ alkyl group, hydroxy group, andcarboxyl group), and optionally-substituted 5- to 10-membered heteroarylgroup (wherein the substituent(s) of said optionally-substituted 5- to10-membered heteroaryl group is one or more substituents selectedindependently from the group consisting of amino group which may besubstituted with one or two the same or different C₁₋₃ alkyl, C₁₋₃ alkylgroup, hydroxy group, and carboxyl group), or the (ii)optionally-substituted C₁₋₃ alkyl group may be any one of the groups offormulae (4)-(6), in formula (4), m is 1, R⁷ is amino acid group (whichbinds to C(O) at its N terminus), in formula (5), q is 1, 2, 3, 4, or 5,L² is single bond or C(O), R⁸ is hydroxy group or amino acid group(which binds to L² at its N terminus), in formula (6), L³ is C(O), R⁹ ishydroxy group or amino acid group (which binds to L³ at its N terminus).38. A method for treating and/or preventing corneal disease, comprisingadministering a therapeutically effective amount of the compound whichis selected from the group consisting of3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid,N-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid,N2-({4-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-arginine,N-{[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}-L-glutamicacid,3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid,N-({4-[({[3-(6,7-dihydroxy-1,2-dimethyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid,3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromene-5-carboxylicacid,N-({4-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)methyl]-1H-1,2,3-triazol-1-yl}acetyl)-L-glutamicacid,N-[({[3-(7,8-dihydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamicacid, andN-[({[3-(6,7-dihydroxy-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)-6,7-dihydroxy-4-oxo-4H-chromen-5-yl]carbonyl}oxy)acetyl]-L-glutamicacid, or a pharmaceutically acceptable salt thereof to a patient in needthereof.